Thiadiazoles as CXC- and CC- chemokine receptor ligands

ABSTRACT

Disclosed are novel compounds of the formula: 
                         
and the pharmaceutically acceptable salts and solvates thereof. Examples of groups comprising Substituent A include heteroaryl, aryl, heterocycloalkyl, cycloalkyl, aryl, alkynyl, alkenyl, aminoalkyl, alkyl or amino. Examples of groups comprising Substituent B include aryl and heteroaryl. Also disclosed is a method of treating a chemokine mediated diseases, such as, cancer, angiogenisis, angiogenic ocular diseases, pulmonary diseases, multiple sclerosis, rheumatoid arthritis, osteoarthritis, stroke and ischemia reperfusion injury, pain (e.g., acute pain, acute and chronic inflammatory pain, and neuropathic pain) using a compound of formula IA.

REFERENCE TO RELATED APPLICATION

This application is a divisional application of U.S. application Ser. No. 11/013,753 filed Dec. 16, 2004, which application in turn claims the benefit of U.S. Provisional Application 60/531,311 filed Dec. 19, 2003, and U.S. Provisional Application 60/531,713 filed Dec. 22, 2003, the disclosures of each being incorporated herein by reference thereto.

FIELD OF THE INVENTION

The present invention relates to novel substituted thiadiazole compounds, pharmaceutical compositions containing the compounds, and the use of the compounds and formulations in treating CXC and CC-chemokine-mediated diseases.

BACKGROUND OF THE INVENTION

Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T-cells, eosinophils, basophils, neutrophils and endothelial cells to sites of inflammation and tumor growth. There are two main classes of chemokines, the CXC-chemokines and the CC-chemokines. The class depends on whether the first two cysteines are separated by a single amino acid (CXC-chemokines) or are adjacent (CC-chemokines). The CXC-chemokines include, but are not limited to, interleukin-8 (IL-8), neutrophil-activating protein-1 (NAP-1), neutrophil-activating protein-2 (NAP-2), GROα, GROβ, GROγ, ENA-78, GCP-2, IP-10, MIG and PF4. CC chemokines include, but are not limited to, RANTES, MIP-1α, MIP-2β, monocyte chemotactic protein-1 (MCP-1), MCP-2, MCP-3, CCL19, CCL21 and eotaxin. Individual members of the chemokine families are known to be bound by at least one chemokine receptor, with CXC-chemokines generally bound by members of the CXCR class of receptors, and CO-chemokines by members of the CCR class of receptors. For example, IL-8 is bound by the CXCR-1 and CXCR-2 receptors.

Since CXC-chemokines promote the accumulation and activation of neutrophils, these chemokines have been implicated in a wide range of acute and chronic inflammatory disorders including psoriasis and rheumatoid arthritis. Baggiolini et al., FEBS Lett. 307, 97 (1992); Miller et al., Crit. Rev. Immunol. 12, 17 (1992); Oppenheim et al., Annu. Fev. Immunol. 9, 617 (1991); Seitz et al., J. Clin. Invest. 87, 463 (1991); Miller et al., Am. Rev. Respir. Dis. 146, 427 (1992); Donnely et al., Lancet 341, 643 (1993).

ELRCXC chemokines including IL-8, GROα, GROβ, GROγ, NAP-2, and ENA-78 (Strieter et al., 1995 JBC 270 p. 27348-57) have also been implicated in the induction of tumor angiogenesis (new blood vessel growth). All of these chemokines are believed to exert their actions by binding to the 7 transmembrane G-protein coupled receptor CXCR2 (also known as IL-8RB), while IL-8 also binds OXCR1 (also known as IL-8RA). Thus, their angiogenic activity is due to their binding to and activation of CXCR2, and possible CXCR1 for IL-8, expressed on the surface of vascular endothelial cells (ECs) in surrounding vessels.

Many different types of tumors have been shown to produce ELRCXC chemokines and their production has been correlated with a more aggressive phenotype (Inoue et al. 2000 Clin Cancer Res 6 p. 2104-2119) and poor prognosis (Yoneda et. al. 1998 J Nat Cancer Inst 90 p. 447-454). Chemokines are potent chemotactic factors and the ELRCXC chemokines have been shown to induce EC chemotaxis. Thus, these chemokines probably induce chemotaxis of endothelial cells toward their site of production in the tumor. This may be a critical step in the induction of angiogenesis by the tumor. Inhibitors of CXCR2 or dual inhibitors of CXCR2 and CXCR1 will inhibit the angiogenic activity of the ELRCXC chemokines and therefore block the growth of the tumor. This anti-tumor activity has been demonstrated for antibodies to IL-8 (Arenberg et al. 1996 J Clin Invest 97 p. 2792-2802), ENA-78 (Arenberg et al. 1998 J Clin Invest 102 p. 465-72), and GROα (Haghnegahdar et al. J. Leukoc Biology 2000 67 p. 53-62).

Many tumor cells have also been shown to express CXCR2 and thus tumor cells may also stimulate their own growth when they secrete ELRCXC chemokines. Thus, along with decreasing angiogenesis, inhibitors of CXCR2 may directly inhibit the growth of tumor cells.

Hence, the CXC-chemokine receptors represent promising targets for the development of novel anti-inflammatory and anti-tumor agents.

There remains a need for compounds that are capable of modulating activity at CXC-chemokine receptors. For example, conditions associated with an increase in IL-8 production (which is responsible for chemotaxis of neutrophil and T-cell subsets into the inflammatory site and growth of tumors) would benefit by compounds that are inhibitors of IL-8 receptor binding.

SUMMARY OF THE INVENTION

This invention provides novel compounds of formula IA:

and the pharmaceutically acceptable salts (e.g., sodium or calcium) thereof, wherein A and B are defined below.

This invention also provides a method of treating a chemokine mediated disease or condition in a patient in need of such treatment comprising administering to said patient an effective amount of at least one compound (usually 1) of formula IA, or a pharmaceutically acceptable salt thereof.

This invention also provides a method of treating a CXCR1 and/or CXCR2 mediated disease or condition in a patient in need of such treatment comprising administering to said patient an effective amount of at least one compound (usually 1) of formula IA, or a pharmaceutically acceptable salt thereof.

This invention also provides a method of treating a CCR7 mediated disease or condition in a patient in need of such treatment comprising administering to said patient an effective amount of at least one compound (usually 1) of formula IA, or a pharmaceutically acceptable salt thereof.

This invention also provides a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of at least one (usually 1) compound of formula IA, or a pharmaceutically acceptable salt thereof.

This invention also provides a method of treating Kaposi's sarcoma, melanoma, gastric carcinoma, and non-small cell carcinoma in a patient in need of such treatment comprising administering to said patient an effective amount of at least one (usually 1) compound of formula IA, or a pharmaceutically acceptable salt thereof.

This invention also provides a method of treating melanoma, gastric carcinoma, and non-small cell carcinoma in a patient in need of such treatment comprising administering to said patient an effective amount of at least one (usually 1) compound of formula IA, or a pharmaceutically acceptable salt thereof.

This invention also provides a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of at least one (usually 1) compound of formula IA, or a pharmaceutically acceptable salt thereof, in combination with at least one anticancer agent selected from the group consisting of: (a) microtubule affecting agents, (b) antineoplastic agents, (c) anti-angiogenesis agents, or (d) VEGF receptor kinase inhibitors, (e) antibodies against the VEGF receptor, (f) interferon, and g) radiation. The compound of formula IA can be administered concurrently or sequentially with the anticancer agent.

This invention also provides a method of treating cancer in a patient in need of such treatment comprising administering to said patient at least one (usually 1) compound of formula IA, or a pharmaceutically acceptable salt thereof, in combination with at least one (usually 1) antineoplastic agent selected from the group consisting of: gemcitabine, paclitaxel (Taxol®), 5-Fluorourcil (5-FU), cyclophosphamide (Cytoxan®), temozolomide, and Vincristine.

This invention also provides a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of at least one (usually 1) compound of formula IA, or a pharmaceutically acceptable salt thereof, concurrently or sequentially with microtubule affecting agent, e.g., paclitaxel.

This invention also provides a method treating cancer in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of: (a) at least one (usually 1) compound of formula IA, or a pharmaceutically acceptable salt thereof, concurrently or sequentially with (b) at least one (usually 1) agent selected from the group consisting of: (1) antineoplastic agents, (2) microtubule affecting agents, and (3) anti-angiogenesis agents.

This invention also provides a method of inhibiting angiogenesis in a patient in need of such treatment comprising administering to said patient an effective amount of at least one (usually 1) compound of formula IA, or a pharmaceutically acceptable salt thereof.

This invention also provides a method of treating angiogenic ocular disease (e.g., ocular inflammation, retinopathy of prematurity, diabetic retinopathy, macular degeneration with the wet type preferred and corneal neovascularization) in a patient in need of such treatment comprising administering to said patient an effective amount of at least one (usually 1) compound of formula IA, or a pharmaceutically acceptable salt thereof.

This invention also provides a method of treating a chemokine mediated (e.g., CXCR1 and/or CXCR2, or CCR7) disease or condition selected from the group consisting of: pain (e.g., acute pain, acute inflammatory pain, chronic inflammatory pain, and neuropathic pain), acute inflammation, chronic inflammation, rheumatoid arthritis, psoriasis, atopic dermatitis, asthma, COPD, adult respiratory disease, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, stroke, ischemia reperfusion injury, renal reperfusion injury, glomerulonephritis, thrombosis, Alzheimer's disease, graft vs. host reaction (i.e., graft vs. host disease), allograft rejections (e.g., acute allograft rejection, and chronic allograft rejection), malaria, acute respiratory distress syndrome, delayed type hypersensitivity reaction, atherosclerosis, cerebral ischemia, cardiac ischemia, osteoarthritis, multiple sclerosis, restinosis, angiogenesis, osteoporosis, gingivitis, respiratory viruses, herpes viruses, hepatitis viruses, HIV, Kaposi's sarcoma associated virus (i.e., Kaposi's sarcoma), meningitis, cystic fibrosis, pre-term labor, cough, pruritus, multi-organ dysfunction, trauma, strains, sprains, contusions, psoriatic arthritis, herpes, encephalitis, CNS vasculitis, traumatic brain injury, CNS tumors, subarachnoid hemorrhage, post surgical trauma, interstitial pneumonitis, hypersensitivity, crystal induced arthritis, acute pancreatitis, chronic pancreatitis, acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis, angiogenic ocular disease, ocular inflammation, retinopathy of prematurity, diabetic retinopathy, macular degeneration with the wet type preferred, corneal neovascularization, polymyositis, vasculitis, acne, gastric ulcers, duodenal ulcers, celiac disease, esophagitis, glossitis, airflow obstruction, airway hyperresponsiveness (i.e., airway hyperreactivity), bronchiectasis, bronchiolitis, bronchiolitis obliterans (i.e., bronchiolitis obliterans syndrome), chronic bronchitis, cor pulmonae, dyspnea, emphysema, hypercapnea, hyperinflation, hypoxemia, hyperoxia-induced inflammations, hypoxia, surgical lung volume reduction, pulmonary fibrosis, pulmonary hypertension, right ventricular hypertophy, peritonitis associated with continuous ambulatory peritoneal dialysis (CAPD), granulocytic ehrlichiosis, sarcoidosis, small airway disease, ventilation-perfusion mismatching, wheeze, colds, gout, alcoholic liver disease, lupus, burn therapy (i.e., the treatment of burns), periodontitis, cancer, transplant reperfusion injury, early transplantation rejection (e.g., acute allograft rejection), airway hyperreactivity, allergic contact dermatitis, allergic rhinitis, alopecia areata, antiphospholipid syndromes, aplastic anemia, autoimmune deafness (including, for example, Meniere's disease), autoimmune hemolytic syndromes, autoimmune hepatitis, autoimmune neuropathy, autoimmune ovarian failure, autoimmune orchitis, autoimmune thrombocytopenia, bullous pemphigoid, chronic allograft vasculopathy, chronic inflammatory demyelinating polyneuropathy, cirrhosis, cor pneumoniae, cryoglobulinemia, dermatomyositis, diabetes, drug-induced autoimmunity, epidermolysis bullosa acquisita, endometriosis, fibrotic diseases, gastritis, Goodpasture's syndrome, Graves' disease, Gullain-Barre disease, Hashimoto's thyroiditis, hepatitis-associated autoimmunity, HIV-related autoimmune syndromes and hematologic disorders, hypophytis, idiopathic thrombocytic pupura, interstitial cystitis, juvenile arthritis, Langerhans' cell histiocytitis, lichen planus, metal-induced autoimmunity, myasthenia gravis, myelodysplastic syndromes, myocarditis (including viral myocarditis), myositis, Neuropathies (including, for example, IgA neuropathy, membranous neuropathy and idiopathic neuropathy), nephritic syndrome, optic neuritis, pancreatitis, paroxysmal nocturnal hemoglobulinemia, pemphigus, polymyalgia, post-infectious autoimmunity, primary biliary cirrhosis, reactive arthritis, ankylosing spondylitis, Raynaud's phenomenon, Reiter's syndrome, reperfusion injury, scleritis, scleroderma, secondary hematologic manifestation of autoimmune diseases (such as, for example, anemias), silicone implant associated autoimmune disease, Sjogren's syndrome, systemic lupus erythematosus, thrombocytopenia, transverse myelitis, tubulointerstitial nephritis, uveitis, vasculitis syndromes (such as, for example, giant cell arteritis, Behcet's disease and Wegener's granulomatosis), and Vitiligo in a patient in need of such treatment comprising administering to said patient an effective amount of at least one compound (usually 1) of formula A, or a pharmaceutically acceptable salt thereof.

This invention also provides a method of treating a CXCR1 and/or a CXCR2 mediated disease or condition selected from the group consisting of: pain (e.g., acute pain, acute inflammatory pain, chronic inflammatory pain, and neuropathic pain), acute inflammation, chronic inflammation, rheumatoid arthritis, psoriasis, atopic dermatitis, asthma, COPD, adult respiratory disease, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, stroke, ischemia reperfusion injury, renal reperfusion injury, glomerulonephritis, thrombosis, Alzheimer's disease, graft vs. host reaction (i.e., graft vs. host disease), allograft rejections (e.g., acute allograft rejection, and chronic allograft rejection), malaria, acute respiratory distress syndrome, delayed type hypersensitivity reaction, atherosclerosis, cerebral ischemia, cardiac ischemia, osteoarthritis, multiple sclerosis, restinosis, angiogenesis, osteoporosis, gingivitis, respiratory viruses, herpes viruses, hepatitis viruses, HIV, Kaposi's sarcoma associated virus (i.e., Kaposis sarcoma), meningitis, cystic fibrosis, pre-term labor, cough, pruritus, multi-organ dysfunction, trauma, strains, sprains, contusions, psoriatic arthritis, herpes, encephalitis, CNS vasculitis, traumatic brain injury, CNS tumors, subarachnoid hemorrhage, post surgical trauma, interstitial pneumonitis, hypersensitivity, crystal induced arthritis, acute pancreatitis, chronic pancreatitis, acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis, angiogenic ocular disease, ocular inflammation, retinopathy of prematurity, diabetic retinopathy, macular degeneration with the wet type preferred, corneal neovascularization, polymyositis, vasculitis, acne, gastric ulcers, duodenal ulcers, celiac disease, esophagitis, glossitis, airflow obstruction, airway hyperresponsiveness (i.e., airway hyperreactivity), bronchiectasis, bronchiolitis, bronchiolitis obliterans, chronic bronchitis, cor pulmonae, dyspnea, emphysema, hypercapnea, hyperinflation, hypoxemia, hyperoxia-induced inflammations, hypoxia, surgical lung volume reduction, pulmonary fibrosis, pulmonary hypertension, right ventricular hypertrophy, peritonitis associated with continuous ambulatory peritoneal dialysis (CAPD), granulocytic ehrlichiosis, sarcoidosis, small airway disease, ventilation-perfusion mismatching, wheeze, colds, gout, alcoholic liver disease, lupus, burn therapy (i.e., the treatment of burns), periodontitis, cancer, transplant reperfusion injury, early transplantation rejection (e.g., acute allograft rejection) in a patient in need of such treatment comprising administering to said patient an effective amount of at least one compound (usually 1) of formula IA, or a pharmaceutically acceptable salt thereof.

This invention also provides a method of treating a CCR7 mediated disease or condition selected from the group consisting of: pain (e.g., acute pain, acute inflammatory pain, chronic inflammatory pain, and neuropathic pain), acute inflammation, chronic inflammation, acute allograft rejection, acute respiratory distress syndrome, adult respiratory disease, airway hyperreactivity, allergic contact dermatitis, allergic rhinitis, alopecia areata, alzheimer's disease, angiogenic ocular disease, antiphospholipid syndromes, aplastic anemia, asthma, atherosclerosis, atopic dermatitis, autoimmune deafness (including, for example, Meniere's disease), autoimmune hemolytic syndromes, autoimmune hepatitis, autoimmune neuropathy, autoimmune ovarian failure, autoimmune orchitis, autoimmune thrombocytopenia, bronchiolitis, bronchiolitis obliterans syndrome, bullous pemphigoid, burn therapy (i.e., the treatment of burns), cancer, cerebral ischemia, cardiac ischemia, chronic allograft rejection, chronic allograft vasculopathy, chronic bronchitis, chronic inflammatory demyelinating polyneuropathy, chronic sinusitis, cirrhosis, CNS vasculitis, COPD, Cor pneumoniae, Crohn's disease, cryoglobulinemia, crystal-induced arthritis, delayed-type hypersensitivity reactions, dermatomyositis, diabetes, diabetic retinopathy, drug-induced autoimmunity, dyspnea, emphysema, epidermolysis bullosa acquisita, endometriosis, fibrotic diseases, gastritis, glomerulonephritis, Goodpasture's syndrome, graft vs host disease, Graves' disease, Gullain-Barre disease, Hashimoto's thyroiditis, hepatitis-associated autoimmunity, HIV-related autoimmune syndromes and hematologic disorders, hyperoxia-induced inflammation, hypercapnea, hyperinflation, hypophytis, hypoxia, idiopathic thrombocytic pupura, inflammatory bowel diseases, interstitial cystitis, interstitial pneumonitis, juvenile arthritis, Langerhans' cell histiocytitis, lichen planus, metal-induced autoimmunity, multiple sclerosis, myasthenia gravis, myelodysplastic syndromes, myocarditis including viral myocarditis, myositis, neuropathies (including, for example, IgA neuropathy, membranous neuropathy and idiopathic neuropathy), nephritic syndrome, ocular inflammation, optic neuritis, osteoarthritis, pancreatitis, paroxysmal nocturnal hemoglobulinemia, pemphigus, polymyalgia, polymyositis, post-infectious autoimmunity, pulmonary fibrosis, primary biliary cirrhosis, psoriasis, pruritus, rheumatoid arthritis, reactive arthritis, ankylosing spondylitis, psoriatic arthritis, Raynaud's phenomenon, Reiter's syndrome, ischemia injury, restenosis, sarcoidosis, scleritis, scleroderma, secondary hematologic manifestation of autoimmune diseases (such as, for example, anemias), silicone implant associated autoimmune disease, Sjogren's syndrome, systemic lupus erythematosus, thrombocytopenia, thrombosis, transverse myelitis, tubulointerstitial nephritis, ulcerative colitis, uveitis, vasculitis and vasculitis syndromes (such as, for example, giant cell arteritis, Behcet's disease and Wegener's granulomatosis), and vitiligo in a patient in need of such treatment comprising administering to said patient an effective amount of at least one compound (usually 1) of formula IA, or a pharmaceutically acceptable salt thereof.

This invention also provides a method of treating a chemokine (e.g., a CXC, or a CC chemokine) mediated disease or condition in a patient in need of such treatment comprising administering to said patient at least one (usually 1) compound of formula IA, or a pharmaceutically acceptable salt thereof, in combination with at least one (usually 1) other medicament (e.g., a drug, agent or therapeutic) useful for the treatment of chemokine mediated diseases.

This invention also provides a method of treating a chemokine mediated disease or condition in a patient in need of such treatment comprising administering to said patient at least one (usually 1) compound of formula IA, or a pharmaceutically acceptable salt thereof, in combination with at least one (usually t) other medicament (e.g., a drug, agent or therapeutic) selected from the group consisting of:

-   -   a) disease modifying antirheumatic drugs;     -   b) nonsteroidal antiinflammatory drugs;     -   c) COX-2 selective inhibitors;     -   d) COX-1 inhibitors;     -   e) immunosuppressives;     -   f) steroids;     -   g) biological response modifiers; and     -   h) other anti-inflammatory agents or therapeutics useful for the         treatment of chemokine mediated diseases.

This invention also provides a method of treating a pulmonary disease (e.g., COPD, asthma or cystic fibrosis) in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one compound (usually 1) of formula IA, or a pharmaceutically acceptable salt thereof, in combination with at least one (usually 1) compound selected from the group consisting of: glucocorticoids, 5-lipoxygenase inhibitors, β-2 adrenoceptor agonists, muscarinic M1 antagonists, muscarinic M3 antagonists, muscarinic M2 agonists, NK3 antagonists, LTB4 antagonists, cysteinyl leukotriene antagonists, bronchodilators, PDE4 inhibitors, PDE inhibitors, elastase inhibitors, MMP inhibitors, phospholipase A2 inhibitors, phospholipase D inhibitors, histamine H1 antagonists, histamine H3 antagonists, dopamine agonists, adenosine A2 agonists, NK1 and NK2 antagonists, GABA-b agonists, nociceptin agonists, expectorants, mucolytic agents, decongestants, antioxidants, anti-IL-8 anti-bodies, anti-IL-5 antibodies, anti-IgE antibodies, anti-TNF antibodies, IL-10, adhesion molecule inhibitors, and growth hormones.

This invention also provides a method of treating multiple sclerosis in a patient in need of such treatment comprising administering to said patient, a therapeutically effective amount of at least one (usually 1) compound of formula IA, or a pharmaceutically acceptable salt thereof, in combination with at least one compound selected from the group consisting of glatiramer acetate, glucocorticoids, methotrexate, azothioprine, mitoxantrone, chemokine inhibitors, and CB2-selective agents.

This invention also provides a method of treating multiple sclerosis in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually 1) compound of formula IA, or a pharmaceutically acceptable salt thereof, in combination with at least one compound selected from the group consisting of: methotrexate, cyclosporin, leflunimide, sulfasalazine, β-methasone, β-interferon, glatiramer acetate, and prednisone.

This invention also provides a method of treating rheumatoid arthritis in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually one) compound of formula IA, or a pharmaceutically acceptable salt thereof.

This invention also provides a method of treating rheumatoid arthritis in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually 1) compound of formula IA, or a pharmaceutically acceptable salt thereof, in combination with at least one compound selected from the group consisting of COX-2 inhibitors, COX inhibitors, immunosuppressives (e.g., methotrexate, cyclosporin, leflunimide and sulfasalazine), steroids (e.g., betamethasone, cortisone and dexamethasone), PDE IV inhibitors, anti-TNF-α compounds, MMP inhibitors, glucocorticoids, chemokine inhibitors, CB2-selective inhibitors, and other classes of compounds indicated for the treatment of rheumatoid arthritis.

This invention also provides a method of treating stroke and ischemia reperfusion injury in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one compound (usually 1) of formula IA, or a pharmaceutically acceptable salt thereof, in combination with at least one compound selected from the group consisting of thrombolitics (e.g., tenecteplase, TPA, alteplase), antiplatelet agents (e.g., gpIIb/IIIa), antagonists (e.g., abciximab and eftiifbatide), anticoagulants (e.g., heparin), and other compounds indicated for the treatment of rheumatoid arthritis.

This invention also provides a method of treating stroke and ischemia reperfusion injury in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually 1) compound of formula IA, or a pharmaceutically acceptable salt thereof, in combination with at least one compound selected from the group consisting of tenecteplase, TPA, alteplase, abciximab, eftiifbatide, and heparin.

This invention also provides a method of treating psoriasis in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually 1) compound of formula IA, or a pharmaceutically acceptable salt thereof, in combination with at least one compound selected from the group consisting of immunosuppressives (e.g., methotrexate, cyclosporin, leflunimide and sulfasalazine), steroids (e.g., β-methasone) and anti-TNF-α compounds (e.g., etonercept and infliximab).

This invention also provides a method of treating COPD in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually one) compound of formula IA, or a pharmaceutically acceptable salt thereof.

This invention also provides a method of treating arthritis in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually one) compound of formula IA, or a pharmaceutically acceptable salt thereof.

This invention also provides a method of treating osteoarthritis in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually one) compound of formula IA, or a pharmaceutically acceptable salt thereof.

This invention also provides a method of treating pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually one) compound of formula IA, or a pharmaceutically acceptable salt thereof.

This invention also provides a method of treating pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually one) compound of formula IA, or a pharmaceutically acceptable salt thereof, and administering a therapeutically effective amount of at least one medicament selected from the group consisting of: NSAIDs, COXIB inhibitors, anti-depressants, and anti-convulsants.

This invention also provides a method of treating acute pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually one) compound of formula IA, or a pharmaceutically acceptable salt thereof.

This invention also provides a method of treating acute inflammatory pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually one) compound of formula IA, or a pharmaceutically acceptable salt thereof.

This invention also provides a method of treating chronic inflammatory pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually one) compound of formula IA, or a pharmaceutically acceptable salt thereof.

This invention also provides a method of treating neuropathic pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually one) compound of formula IA, or a pharmaceutically acceptable salt thereof.

This invention also provides a pharmaceutical composition comprising at least one (e.g., 1-3, usually 1) compound of formula IA, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

This invention also provides a pharmaceutical composition comprising at least one (e.g., 1-3, usually 1) compound of formula IA, or a pharmaceutically acceptable to salt thereof, and at least one (e.g., 1-3, usually 1) other agent, medicament, antibody and/or inhibitor disclosed above, and a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

When any variable occurs more than one time in any moiety, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

Unless indicated otherwise, the following definitions apply throughout the present specification and claims. These definitions apply regardless of whether a term is used by itself or in combination with other terms. For example, the definition of “alkyl” also applies to the “alkyl” portion of “alkoxy”.

“An effective amount” means a therapeutically acceptable amount (i.e., that amount which provides the desired therapeutic effective).

“At least one” means one or more (e.g., 1-3, 1-2, or 1).

“Bu” represents butyl.

“Bn” represents benzyl.

“Composition” includes a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

“Et” represents ethyl.

“In combination with” as used to describe the administration of a compound of formula IA with other medicaments in the methods of treatment of this invention, means that the compounds of formula IA and the other medicaments are administered sequentially or concurrently in separate dosage forms, or are administered concurrently in the same dosage form.

“Mammal” includes a human being, and preferably means a human being.

“Patient” includes both human and other mammals, preferably human.

“Ph”, as used in the structures herein, represents phenyl.

“Pr” represents propyl.

“Prodrug” represents compounds that are rapidly transformed in vivo to the compound of formula IA, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

“Alkyl” means a straight or branched saturated hydrocarbon chain having 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms.

“Alkoxy” means an alkyl-O— group wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, n-propoxy, iso-propoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen.

“Alkenyl” means a straight or branched aliphatic hydrocarbon group having at least one carbon-carbon double bond, and 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, and more preferably 2 to 6 carbon atoms. Non-limiting examples of alkenyl groups include: ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

“Alkynyl” means a straight or branched aliphatic hydrocarbon group having at least one carbon-carbon triple bond, and 2 to 15 carbon atoms, preferably 2 to 12 carbon atoms, and more preferably 2 to 4 carbon atoms. Non-limiting examples of alkynyl groups include ethynyl, propynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, and decynyl.

“Aryl” means an aromatic monocyclic or multicyclic ring system, wherein at least one ring is aromatic, comprising about 6 to about 14 carbon atoms, and preferably about 6 to about 10 carbon atoms. Non-limiting examples of suitable aryl groups include: phenyl, naphthyl, indenyl, tetrahydronaphthyl, indanyl, anthracenyl, and fluorenyl.

“Arylalkyl” means an aryl group, as defined above, bound to an alkyl group, as defined above, wherein the alkyl group is bound to the parent moiety. Non-limiting examples of suitable arylalkyl groups include benzyl, phenethyl and naphthleneylmethyl.

“Bn” represents benzyl

“Cycloalkyl” means saturated carbocyclic rings having 3 to 10 (e.g., 3 to 7) carbon atoms, preferably 5 to 10 carbon atoms, and more preferably 5 to 7 carbon atoms, and having one to three rings. Non-limiting examples of cycloalkyl groups include: cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl.

“Cycloalkylalkyl” means a cycloalkyl group bound to the parent moiety through an alkyl group. Non-limiting examples include: cyclopropylmethyl and cyclohexylmethyl.

“Cycloalkenyl” means a non-aromatic mono or multicyclic ring system comprising 3 to 10 carbon atoms, and preferably 5 to 10 carbon atoms, and having at least one carbon-carbon double bond. Preferred cycloalkenyl rings have 5 to 7 carbon atoms. Non-limiting examples of cycloalkyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, and norbornenyl.

“Et” represents ethyl,

“Halo” means fluoro, chloro, bromo, or iodo groups. Preferred are fluoro, chloro or bromo, and more preferred are fluoro and chloro.

“Halogen” means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine or bromine, and more preferred are fluorine and chlorine.

“Haloalkyl” means an alkyl group as defined above wherein one or more hydrogen atoms on the alkyl is replaced by a halo group defined above.

“Heterocyclyl” or “heterocyclic” or “heterocycloalkyl” means a non-aromatic saturated monocyclic or multicyclic ring system (i.e., a saturated carbocyclic ring or ring system) comprising 3 to 10 ring atoms (e.g., 3 to 7 ring atoms), preferably 5 to 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls have 5 to 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or SS-dioxide. Non-limiting examples of monocyclic heterocyclyl rings include: piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl.

The term heterocyclic acidic functional group is intended to include groups such as, pyrrole, imidazole, triazole, tetrazole, and the like.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring system comprising 5 to 14 ring atoms, preferably 5 to 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain 5 to 6 ring atoms. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide Non-limiting examples of heteroaryls include: pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, and benzothiazolyl.

“Heteroarylalkyl” means a heteroaryl group, as defined above, bound to an alkyl group, as defined above, where the bond to the parent moiety is through the alkyl group.

“Solvate” means a physical association of a compound of this invention with one or more solvent molecules; This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding; In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid; “Solvate” encompasses both solution-phase and isolatable solvates; Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like; “Hydrate” is a solvate wherein the solvent molecule is H₂O.

The term “pharmaceutical composition” is also intended to encompass both the bulk composition and individual dosage units comprised of more than one (e.g., two) pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients. The bulk composition and each individual dosage unit can contain fixed amounts of the afore-said “more than one pharmaceutically active agents”. The bulk composition is material that has not yet been formed into individual dosage units. An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like. Similarly, the herein-described method of treating a patient by administering a pharmaceutical composition of the present invention is also intended to encompass the administration to of the afore-said bulk composition and individual dosage units.

N-oxides can form on a tertiary nitrogen present in an R substituent, or on ═N— in a heteroaryl ring substituent and are included in the compounds of formula IA.

As well known in the art, a bond drawn from a particular atom wherein no moiety is depicted at the terminal end of the bond indicates a methyl group bound through that bond to the atom. For example:

The compounds of this invention are represented by formula IA:

and the pharmaceutically acceptable salts (e.g., sodium or calcium salt) thereof, wherein:

A is selected from the group consisting of:

wherein the above rings of said A groups are substituted with 1 to 6 substituents each independently selected from the group consisting of: R⁹ groups;

wherein one or both of the above rings of said A groups are substituted with 1 to 6 substituents each independently selected from the group consisting of: R⁹ groups;

wherein the above phenyl rings of said A groups are substituted with 1 to 3 substituents each independently selected from the group consisting of: R⁹ groups; and

B is selected from the group consisting of

n is 0 to 6;

p is 1 to 5

X is O, NR¹⁸, or S;

Z is 1 to 3;

R² is selected from the group consisting of: hydrogen, OH, —C(O)OH, —SH, —SO₂NR¹³R¹⁴, —NHC(O)R¹³, —NHSO₂NR¹³R¹⁴, —NHSO₂R¹³, —NR¹³R¹⁴, —C(O)NR¹³R¹⁴, —C(O)NHOR¹³, —C(O)NR¹³OH, —S(O₂)OH, —OC(O)R¹³, an unsubstituted heterocyclic acidic functional group, and a substituted heterocyclic acidic functional group; wherein there are 1 to 6 substituents on said substituted heterocyclic acidic functional group each substituent being independently selected from the group consisting of: R⁹ groups;

each R³ and R⁴ is independently selected from the group consisting of: hydrogen, cyano, halogen, alkyl, cycloalkyl substituted with 1 to 4 alkyl groups (preferably C₁ to C₆ alkyl groups) wherein each alkyl group is independently selected, unsubstituted cycloalkyl, alkoxy, —OH, —CF₃, —OCF₃, —NO₂, —C(O)R¹³, —C(O)OR¹³, —C(O)NHR¹⁷, —C(O)NR¹³R¹⁴, —SO_((t))NR¹³R¹⁴, —SO_((t))R¹³, —C(O)NR¹³OR¹⁴, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl,

wherein there are 1 to 6 substituents on said substituted aryl group and each substituent is independently selected from the group consisting of: R⁹ groups; and wherein there are 1 to 6 substituents on said substituted heteroaryl group and each substituent is independently selected from the group consisting of: R⁹ groups; or

R³ is and R⁴ taken together with the carbons atoms to which they are bonded to in the phenyl B substituent

form a fused ring of the formula:

(preferably Z¹) wherein Z¹ or Z² is an unsubstituted or substituted saturated heterocyclic ring (preferably a 4 to 7 membered heterocyclic ring), said ring Z¹ or Z² optionally containing one additional heteroatom selected from the group consisting of: O, S and NR¹⁸; wherein there are 1 to 3 substituents on said ring Z¹ or Z², and each substituent is independently selected from the group consisting of: alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, —C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵ provided that R¹⁵ is not H, —NHC(O)NR¹⁵R¹⁶, —NHCO(O)OR¹⁵, halogen, and a heterocycloalkenyl group (i.e., a heterocyclic group that has at least one, and preferably one, double bond in a ring, e.g.,

examples of the fused ring moiety include, but are not limited to:

each R⁵ and R⁶ are the same or different and are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, —CF₃, —OCF₃, —NO₂, —C(O)R¹³, —C(O)OR¹³, —C(O)NR¹³R¹⁴, —SO_((t))NR¹³R¹⁴, —C(O)NR¹³OR¹⁴, cyano, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl group; wherein there are 1 to 6 substituents on said substituted aryl group and each substituent is independently selected from the group consisting of: R⁹ groups; and wherein there are 1 to 6 substituents on said substituted heteroaryl group and each substituent is independently selected from the group consisting of: R⁹ groups;

each R⁷ and R⁸ is independently selected from the group consisting of: H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, —CO₂R¹³, —CONR¹³R¹⁴, alkynyl, alkenyl, and cycloalkenyl; and wherein there are one or more (e.g., 1 to 6) substituents on said substituted R⁷ and R⁸ groups, wherein each substitutent is independently selected from the group consisting of:

-   -   a) halogen,     -   b) CF₃,     -   d) —OR¹³,     -   e) —NR¹³R¹⁴,     -   f) —NO₂,     -   g) —CN,     -   h) —SO₂OR¹³,     -   i) —Si(alkyl)₃, wherein each alkyl is independently selected,     -   j) —Si(aryl)₃, wherein each alkyl is independently selected,     -   k) —(R¹³)₂R¹⁴Si, wherein each R¹³ is independently selected,     -   l) —CO₂R¹³,     -   m) —(O)NR¹³R¹⁴,     -   n) —SO₂NR¹³R¹⁴,     -   o) —SO₂R¹³,     -   p) —OC(O)R¹³,     -   q) —OC(O)NR¹³R¹⁴,     -   r) —NR¹³C(O)R¹⁴, and     -   s) —NR¹³CO₂R¹⁴;         (fluoroalkyl is one non-limiting example of an alkyl group that         is substituted with halogen);

R^(8a) is selected from the group consisting of: hydrogen, alkyl, cycloalkyl and cycloalkylalkyl;

each R⁹ is independently selected from the group consisting of:

-   -   a) —R¹³,     -   b) halogen,     -   c) —CF₃,     -   d) —OR¹³,     -   e) —OR¹³,     -   f) —NR¹³R¹⁴,     -   g) —NO₂,     -   h) —CN,     -   j) —SO₂NR¹³R¹⁴,     -   k) —NR¹³COR¹⁴,     -   l) —CONR¹³R¹⁴,     -   m) —NR¹³CO₂R¹⁴,     -   n) —CO₂R¹³,     -   o)

-   -   p) alkyl substituted with one or more (e.g., one) —OH groups         (e.g., —(CH₂)_(q)OH, wherein q is 1-6, usually 1 to 2, and         preferably 1),     -   q) alkyl substituted with one or more (e.g., one) —NR¹³R¹⁴ group         (e.g., —(CH₂)_(q)NR¹³R¹⁴, wherein q is 1-6, usually 1 to 2, and         preferably 1), and     -   r) —N(R¹³)SO₂R¹⁴ (e.g., R¹³ is H and R¹⁴ is alkyl, such as         methyl);

each R¹⁰ and R¹¹ is independently selected from the group consisting of R¹³, (e.g., hydrogen and alkyl (e.g., C₁ to C₆ alkyl, such as methyl)), halogen, —CF₃, —OCF₃, —NR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —OH, —C(O)OR¹³, —SH, —SO_((t))NR¹³R¹⁴, —SO₂R¹³, —NHC(O)R¹³, —NHSO₂NR¹³R¹⁴, —NHSO₂R¹³, —C(O)NR¹³R¹⁴, —C(O)NR¹³OR¹⁴C, —OC(O)R¹³ and cyano;

R¹² is selected from the group consisting of: hydrogen, —C(O)OR¹³, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkylalkyl, and unsubstituted or substituted heteroarylalkyl group; wherein there are 1 to 6 substituents on the substituted R¹² groups and each substituent is independently selected from the group consisting of: R⁹ groups;

each R¹³ and R¹⁴ is independently selected from the group consisting of: H, unsubstituted or substituted alkyl, unsubstituted or substituted cyanoalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cyanocycloalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted fluoroalkyl, and unsubstituted or substituted heterocycloalkylalkyl (wherein “heterocloalkyl” means heterocyclic); wherein there are 1 to 6 substituents on said substituted R¹³ and R¹⁴ groups and each substituent is independently selected from the group consisting of: alkyl, —CF₃, —OH, alkoxy, aryl, arylalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, —N(R⁴⁰)₂, —C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —S(O)_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, halogen, —NHC(O)NR¹⁵R¹⁶ and —SO₂R¹⁵ provided that R¹⁵ is not H; and provided that for the substituted cyanoalkyl and the substituted cyanocycloalkyl moieties the carbon atom to which the cyano (CN) group is bound to does not also have bound to said carbon atom a substituent selected from the group consisting of, —OH, alkoxy, —N(R⁴⁰)₂, halogen and —NHC(O)NR¹⁵R¹⁶; or

R¹³ and R¹⁴ taken together with the nitrogen they are attached to in the groups —C(O)NR¹³R¹⁴ and —SO₂NR¹³R¹⁴ form an unsubstituted or substituted saturated heterocyclic ring (preferably a 3 to 7 membered heterocyclic ring), said ring optionally containing one additional heteroatom selected from the group consisting of: O, S and NR¹⁸; wherein there are 1 to 3 substituents on the substituted cyclized R¹³ and R¹⁴ groups (i.e., there is 1 to 3 substituents on the ring formed when the R¹³ and R¹⁴ groups are taken together with the nitrogen to which they are bound) and each substituent is independently selected from the group consisting of: CN, alkyl, cyanoalkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, cyanocycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, —C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵ (provided that R¹⁵ is not H), —NHC(O)NR¹⁵R¹⁶, —NHC(O)OR¹⁵, halogen, and a heterocycloalkenyl group (i.e., a heterocyclic group that has at least one, and preferably one, double bond in a ring, e.g.,

and provided that the carbon atom to which the cyano (CN) group is bound to does not also have bound to said carbon atom a substituent selected from the group consisting of: hydroxy, alkoxy, amino, halogen, —NHC(O)NR¹⁵R¹⁶ and —NHC(O)OR¹⁵;

(or in another embodiment, (1) each R¹³ and R¹⁴ is independently selected from the group consisting of: H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted fluoroalkyl, and unsubstituted or substituted heterocycloalkylalkyl (wherein “heterocyloalkyl” means heterocyclic); wherein there are 1 to 6 substituents on said substituted R¹³ and R¹⁴ groups and each substituent is independently selected from the group consisting of: alkyl, —CF₃, —OH, alkoxy, aryl, arylalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, —N(R⁴⁰)₂, —C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —S(O)_(t)NR¹⁵R¹⁶; —C(O)R¹⁵, —SO₂R¹⁵ provided that R¹⁵ is not H, halogen, and —NHC(O)NR¹⁵R¹⁶, or (2) R¹³ and R¹⁴ taken together with the nitrogen they are attached to in the groups —C(O)NR¹³R¹⁴ and —SO₂NR¹³R¹⁴ form an unsubstituted or substituted saturated heterocylic ring (preferably a 3 to 7 remembered heterocyclic ring), said ring optionally containing one additional heteroatom selected from the group consisting of: O, S and NR¹⁸; wherein there are 1 to 3 substituents on the substituted cyclized R¹³ and R¹⁴ groups (i.e., there is 1 to 3 substituents on the ring formed when the R¹³ and R¹⁴ groups are taken together with the nitrogen to which they are bound) and each substituent is independently selected from the group consisting of: alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, —C(O)OR⁵, —C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵ (provided that R¹⁵ is not H), —NHC(O)NR¹⁵R¹⁶, —NHC(O)OR¹⁵, halogen, and a heterocycloalkenyl group (i.e., a heterocyclic group that has at least one, and preferably one, double bond in a ring, e.g.,

each R¹⁵ and R¹⁶ is independently selected from the group consisting of: H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl;

R¹⁷ is selected from the group consisting of: —SO₂alkyl, —SO₂aryl, —SO₂cycloalkyl, and —SO₂heteroaryl;

R¹⁸ is selected from the group consisting of: H, alkyl, aryl, heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹ and —C(O)NR¹⁹R²⁰;

each R¹⁹ and R²⁰ is independently selected from the group consisting of: alkyl, aryl and heteroaryl;

R³⁰ is selected from the group consisting of: alkyl, cycloalkyl, —CN, —NO₂, or —SO₂R¹⁵ provided that R¹⁵ is not H;

each R³¹ is independently selected from the group consisting of: unsubstituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl and unsubstituted or substituted cycloalkyl; wherein there are 1 to 6 substituents on said substituted R³¹ groups and each substituent is independently selected from the group consisting of: alkyl, halogen and —CF₃;

each R⁴⁰ is independently selected from the group consisting of: H, alkyl and cycloalkyl; and

t is 0, 1 or 2.

For compounds of formula IA, when R³ is —SO_((t))NR¹³R¹⁴ (e.g., —SO₂NR¹³R¹⁴), preferably R¹³ and R¹⁴ are independently selected from the group consisting of: H and alkyl (e.g., methyl, ethyl, isopropyl and t-butyl). Examples include, but are not limited to (1) —SO₂NH₂ and (2) —SO₂NR¹³R¹⁴ wherein R¹³ and R¹⁴ are the same or different alkyl group (e.g., methyl, ethyl, isopropyl and t-butyl), e.g., the same alkyl group, such as, for example —SO₂N(CH₃)₂.

For compounds of formula IA, when R³ is —C(O)NR¹³R¹⁴, preferably R¹³ and R¹⁴ are independently selected from the group consisting of: H and alkyl (e.g., methyl, ethyl, isopropyl and t-butyl). Examples include, but are not limited to —C(O)NR¹³R¹⁴ wherein each R¹³ and R¹⁴ are the same or different alkyl group, e.g., the same alkyl group, such as, for example —C(O)N(CH₃)₂.

For the compounds of formula IA substituent A is preferably selected from the group consisting of:

wherein all substitutents are as defined for formula IA.

For the compounds of formula IA substituent A is most preferably:

wherein the furan ring is unsubstituted or substituted with 1 or 2 alkyl groups (e.g., C₁ to C₃ alkyl groups) wherein each alkyl group is independently selected, R⁷ is selected from the group consisting of: —CF₃, alkyl (e.g., C₁ to C₄ alkyl) and cycloalkyl (e.g., cyclopropyl), and R⁸ is H. More preferably the furan ring is substituted.

For the compounds of formula IA substituent A is even more preferably:

wherein the furan ring is unsubstituted or substituted with 1 or 2 alkyl groups independently selected from the group consisting of methyl, ethyl and isopropyl, R⁷ is selected from the group consisting of: CF₃, ethyl, isopropyl, t-butyl and cyclopropyl, and R⁸ is H. Still more preferably the furan ring is substituted.

For the compounds of formula IA substituent A is even yet more preferably:

wherein the furan ring is substituted with 1 or 2 alkyl groups independently selected from the group consisting of methyl, ethyl and isopropyl, RF is selected from the group consisting of: ethyl, isopropyl and t-butyl, and R⁸ is H.

Examples of substituent A in formula IA include, but are not limited to:

Substituent A in formula IA is most preferably selected from the group consisting of:

Substituent A in formula IA is more preferably selected from the group consisting of:

Substituent A in formula IA is even more preferably selected from the group consisting of:

Substituent B in formula IA is preferably selected from the group consisting of:

wherein all substituents are as defined for formula IA.

Substituent B in formula IA is most preferably selected from the group consisting of:

Substituent B in Formula IA is more preferably selected from the group consisting of:

Substituent B in Formula IA is even more preferably selected from the group consisting of:

Substituent B in Formula IA is still even more preferably selected from the group consisting of:

An embodiment of the present invention is directed to a method of treating an chemokine mediated disease in a patient in need of such treatment (e.g., a mammal, to preferably a human being) comprising administering to said patient a therapeutically effective amount of at least one (e.g., 1-3, and usually one) compound of formula IA, or a pharmaceutically acceptable salt thereof.

Examples of chemokine mediated (e.g., CXCR1 and/or CXCR2, or CCR7) diseases or conditions include but are not limited to: pain (e.g., acute pain, acute inflammatory pain, chronic inflammatory pain, and neuropathic pain), rheumatoid arthritis, acute inflammatory pain, chronic inflammatory pain, psoriasis, atopic dermatitis, asthma, COPD, adult respiratory disease, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, stroke, ischemia reperfusion injury, renal reperfusion injury, glomerulonephritis, thrombosis, Alzheimer's disease, graft vs. host reaction (i.e., graft vs. host disease), allograft rejections (e.g., acute allograft rejection, and chronic allograft rejection), malaria, acute respiratory distress syndrome, delayed type hypersensitivity reaction, atherosclerosis, cerebral ischemia, cardiac ischemia, osteoarthritis, multiple sclerosis, restinosis, angiogenesis, osteoporosis, gingivitis, respiratory viruses, herpes viruses, hepatitis viruses, HIV, Kaposi's sarcoma associated virus (i.e., Kaposi's sarcoma), meningitis, cystic fibrosis, pre-term labor, cough, pruritus, multi-organ dysfunction, trauma, strains, sprains, contusions, psoriatic arthritis, herpes, encephalitis, CNS vasculitis, traumatic brain injury, CNS tumors, subarachnoid hemorrhage, post surgical trauma, interstitial pneumonitis, hypersensitivity, crystal induced arthritis, acute pancreatitis, chronic pancreatitis, acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis, angiogenic ocular disease, ocular inflammation, retinopathy of prematurity, diabetic retinopathy, macular degeneration with the wet type preferred, corneal neovascularization, polymyositis, vasculitis, acne, gastric ulcers, duodenal ulcers, celiac disease, esophagitis, glossitis, airflow obstruction, airway hyperresponsiveness (i.e., airway hyperreactivity), bronchiectasis, bronchiolitis, bronchiolitis obliterans, chronic bronchitis, cor pulmonae, dyspnea, emphysema, hypercapnea, hyperinflation, hypoxemia, hyperoxia-induced inflammations, hypoxia, surgical lung volume reduction, pulmonary fibrosis, pulmonary hypertension, right ventricular hypertrophy, peritonitis associated with continuous ambulatory peritoneal dialysis (CAPD), granulocytic ehrlichiosis, sarcoidosis, small airway disease, ventilation-perfusion mismatching, wheeze, colds, gout, alcoholic liver disease, lupus, burn therapy (i.e., the treatment of burns), periodontitis, cancer, transplant reperfusion injury, early transplantation rejection (e.g., acute allograft rejection), airway hyperreactivity, allergic contact dermatitis, allergic rhinitis, alopecia areata, antiphospholipid syndromes, aplastic anemia, autoimmune deafness (including, for example, Meniere's disease), autoimmune hemolytic syndromes, autoimmune hepatitis, autoimmune neuropathy, autoimmune ovarian failure, autoimmune orchitis, autoimmune thrombocytopenia, bullous pemphigoid, chronic allograft vasculopathy, chronic inflammatory demyelinating polyneuropathy, cirrhosis, cor pneumoniae, cryoglobulinemia, dermatomyositis, diabetes, drug-induced autoimmunity, epidermolysis bullosa acquisita, endometriosis, fibrotic diseases, gastritis, Goodpasture's syndrome, Graves' disease, Gullain-Barre disease, Hashimoto's thyroiditis, hepatitis-associated autoimmunity, HIV-related autoimmune syndromes and hematologic disorders, hypophytis, idiopathic thrombocytic pupura, interstitial cystitis, juvenile arthritis, Langerhans' cell histiocytitis, lichen planus, metal-induced autoimmunity, myasthenia gravis, myelodysplastic syndromes, myocarditis (including viral myocarditis), myositis, Neuropathies (including, for example, IgA neuropathy, membranous neuropathy and idiopathic neuropathy), nephritic syndrome, optic neuritis, pancreatitis, paroxysmal nocturnal hemoglobulinemia, pemphigus, polymyalgia, post-infectious autoimmunity, primary biliary cirrhosis, reactive arthritis, ankylosing spondylitis, Raynaud's phenomenon, Reiter's syndrome, reperfusion injury, scleritis, scleroderma, secondary hematologic manifestation of autoimmune diseases (such as, for example, anemias), silicone implant associated autoimmune disease, Sjogren's syndrome, systemic lupus erythematosus, thrombocytopenia, transverse myelitis, tubulointerstitial nephritis, uveitis, vasculitis syndromes (such as, for example, giant cell arteritis, Behcet's disease and Wegener's granulomatosis), and Vitiligo.

Examples of CXCR1 and/or CXCR2 mediated diseases or conditions include but are not limited to: pain (e.g., acute pain, acute inflammatory pain, chronic inflammatory pain, and neuropathic pain), acute inflammation, chronic inflammation, rheumatoid arthritis, psoriasis, atopic dermatitis, asthma, COPD, adult respiratory disease, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, stroke, ischemia reperfusion injury, renal reperfusion injury, glomerulonephritis, thrombosis, Alzheimer's disease, graft vs. host reaction (i.e., graft vs. host disease), allograft rejections (e.g., acute allograft rejection, and chronic allograft rejection), malaria, acute respiratory distress syndrome, delayed type hypersensitivity reaction, atherosclerosis, cerebral ischemia, cardiac ischemia, osteoarthritis, multiple sclerosis, restinosis, angiogenesis, osteoporosis, gingivitis, respiratory viruses, herpes viruses, hepatitis viruses, HIV, Kaposi's sarcoma associated virus (i.e., Kaposi's sarcoma), meningitis, cystic fibrosis, pre-term labor, cough, pruritus, multi-organ dysfunction, trauma, strains, sprains, contusions, psoriatic arthritis, herpes, encephalitis, CNS vasculitis, traumatic brain injury, GNS tumors, subarachnoid hemorrhage, post surgical trauma, interstitial pneumonitis, hypersensitivity, crystal induced arthritis, acute pancreatitis, chronic pancreatitis, acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis, angiogenic ocular disease, ocular inflammation, retinopathy of prematurity, diabetic retinopathy, macular degeneration with the wet type preferred, corneal neovascularization, polymyositis, vasculitis, acne, gastric ulcers, duodenal ulcers, celiac disease, esophagitis, glossitis, airflow obstruction, airway hyperresponsiveness (i.e., airway hyperreactivity), bronchiectasis, bronchiolitis, bronchiolitis obliterans, chronic bronchitis, cor pulmonae, dyspnea, emphysema, hypercapnea, hyperinflation, hypoxemia, hyperoxia-induced inflammations, hypoxia, surgical lung volume reduction, pulmonary fibrosis, pulmonary hypertension, right ventricular hypertrophy, peritonitis associated with continuous ambulatory peritoneal dialysis (CAPD), granulocytic ehrlichiosis, sarcoidosis, small airway disease, ventilation-perfusion mismatching, wheeze, colds, gout, alcoholic liver disease, lupus, burn therapy (i.e., the treatment of burns), periodontitis, cancer, transplant reperfusion injury, early transplantation rejection (e.g., acute allograft rejection).

Examples of CCR7 mediated diseases or conditions include, but are not limited to: pain (e.g., acute pain, acute inflammatory pain, chronic inflammatory pain, and neuropathic pain), acute inflammation, chronic inflammation, acute allograft rejection, acute respiratory distress syndrome, adult respiratory disease, airway hyperreactivity, allergic contact dermatitis, allergic rhinitis, alopecia areata, alzheimer's disease, angiogenic ocular disease, antiphospholipid syndromes, aplastic anemia, asthma, atherosclerosis, atopic dermatitis, autoimmune deafness (including, for example, Meniere's disease), autoimmune hemolytic syndromes, autoimmune hepatitis, autoimmune neuropathy, autoimmune ovarian failure, autoimmune orchitis, autoimmune thrombocytopenia, bronchiolitis, bronchiolitis obliterans syndrome, bullous pemphigoid, burn therapy (i.e., the treatment of burns), cancer, cerebral ischemia, cardiac ischemia, chronic allograft rejection, chronic allograft vasculopathy, chronic bronchitis, chronic inflammatory demyelinating polyneuropathy, chronic sinusitis, cirrhosis, CNS vasculitis, COPD, Cor pneumoniae, Crohn's disease, cryoglobulinemia, crystal-induced arthritis, delayed-type hypersensitivity reactions, dermatomyositis, diabetes, diabetic retinopathy, drug-induced autoimmunity, dyspnea, emphysema, epidermolysis bullosa acquisita, endometriosis, fibrotic diseases, gastritis, glomerulonephritis, Goodpasture's syndrome, graft vs host disease, Graves' disease, Gullain-Barre disease, Hashimoto's thyroiditis, hepatitis-associated autoimmunity, HIV-related autoimmune syndromes and hematologic disorders, hyperoxia-induced inflammation, hypercapnea, hyperinflation, hypophytis, hypoxia, idiopathic thrombocytic pupura, inflammatory bowel diseases, interstitial cystitis, interstitial pneumonitis, juvenile arthritis, Langerhans' cell histiocytitis, lichen planus, metal-induced autoimmunity, multiple sclerosis, myasthenia gravis, myelodysplastic syndromes, myocarditis including viral myocarditis, myositis, neuropathies (including, for example, IgA neuropathy, membranous neuropathy and idiopathic neuropathy), nephritic syndrome, ocular inflammation, optic neuritis, osteoarthritis, pancreatitis, paroxysmal nocturnal hemoglobulinemia, pemphigus, polymyalgia, polymyositis, post-infectious autoimmunity, pulmonary fibrosis, primary biliary cirrhosis, psoriasis, pruritus, rheumatoid arthritis, reactive arthritis, ankylosing spondylitis, psoriatic arthritis, Raynaud's phenomenon, Reiter's syndrome, reperfusion injury, restenosis, sarcoidosis, scleritis, scleroderma, secondary hematologic manifestation of autoimmune diseases (such as, for example, anemias), silicone implant associated autoimmune disease, Sjogren's syndrome, systemic lupus erythematosus, thrombocytopenia, thrombosis, transverse myelitis, tubulointerstitial nephritis, ulcerative colitis, uveitis, vasculitis and vasculitis syndromes (such as, for example, giant cell arteritis, Behcet's disease and Wegener's granulomatosis), and vitiligo.

Another embodiment of this invention is directed to a method of treating a CXCR1 and/or CXCR2 mediated disease or condition, as described above, in a patient in need of such treatment comprising administering to said patient an effective amount of a compound selected from the group consisting of the final compounds of Examples 1-11, 19, 20, 24-28, 31 and 32 and the pharmaceutically acceptable salts thereof.

Another embodiment of this invention is directed to a method of treating a CCR7 mediated disease or condition, as described above, in a patient in need of such treatment comprising administering to said patient an effective amount of a compound selected from the group consisting of the final compounds of Examples 6, 31 and 32, and the pharmaceutically acceptable salts thereof.

In another embodiment this invention is directed to a method of treating pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually one) compound of this invention, or a pharmaceutically acceptable salt thereof. Examples of pain include, but are not limited to, the pain associated with: allodynia, ankylosing spondylitis, appendicitis, autoimmune disorders, bacterial infections, Behcet's syndrome, broken bones, bronchitis, burns, bursitis, cancer including metastatic cancer, candidiasis, cardiovascular conditions, casualgia, chemical injury, childbirth (e.g., labor), chronic regional neuropathies, Crohn's disease, colorectal cancer, connective tissue injuries, conjunctivitis, COPD, decreased intracranial pressure, dental procedures, dermatitis, diabetes, diabetic neuropathy, dysesthesia, dysmenorrhea, eczema, emphysema, fever, fibromyalgia, gastric ulcer, gastritis, giant cell arteritis, gingivitis, gout, gouty arthritis, headache, headache pain resulting from lumbar puncture, headaches including migraine headache, herpes simplex virus infections, HIV, Hodgkin's disease, hyperalgesia, hypersensitivity, inflammatory bowel disease, increased intracranial pressure, irritable bowel syndrome, ischemia, juvenile arthritis, kidney stones, lumbar spondylanhrosis, lower back, upper back and lumbrosacral conditions, lumbar spondylarthrosis, menstrual cramps, migraines, minor injuries, multiple sclerosis, myasthenia gravis, myocarditis, muscle strains, musculoskeletal conditions, myocardial ischemia, nephritic syndrome, nerve root avulsion, neuritis, nutritional deficiency, ocular and corneal conditions, ocular photophobia, ophthalmic diseases, osteoarthritis, otic surgery, otitis externa, otitis media, periarteritis nodosa, peripheral neuropathies, phantom limb pain, polymyositis, post-herpetic neuralgia, post-operative/surgical recovery, post-thoracotomy, psoriatic arthritis, pulmonary fibrosis, pulmonary edema, radiculopathy, reactive arthritis, reflex sympathetic dystrophy, retinitis, retinopathies, rheumatic fever, rheumatoid arthritis, sarcoidosis, sciatica, scleroderma, sickle cell anemia, sinus headaches, sinusitis, spinal cord injury, spondyloarthropathies, sprains, stroke, swimmer's ear, tendonitis, tension headaches, thalamic syndrome, thrombosis, thyroiditis, toxins, traumatic injury, trigeminal neuralgia, ulcerative colitis, urogenital conditions, uveitis, vaginitis, vascular diseases, vasculitis, viral infections and/or wound healing.

In another embodiment this invention is directed to a method of treating pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually one) compound of this invention, or the pharmaceutically acceptable salts thereof, and administering to said patient a therapeutically effective amount of at least one medicament selected from the group consisting of: NSAIDs, COXIB inhibitors, anti-depressants and anti-convulsants. Examples of the pain treatable are described above.

In another embodiment this invention is directed to a method of treating pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually one) compound of this invention, or the pharmaceutically acceptable salts thereof, and administering to said patient a therapeutically effective amount of at least one NSAIDs. Examples of the pain treatable are described above.

In another embodiment this invention is directed to a method of treating pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually one) compound of this invention, or the pharmaceutically acceptable salts thereof, and administering to said patient a therapeutically effective amount of at least one COXIB inhibitor. Examples of the pain treatable are described above.

In another embodiment this invention is directed to a method of treating pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually one) compound of this invention, or the pharmaceutically acceptable salts thereof, and administering to said patient a therapeutically effective amount of at least one anti-depressant. Examples of the pain treatable are described above.

In another embodiment this invention is directed to a method of treating pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually one) compound of this invention, or the pharmaceutically acceptable salts thereof, and administering to said patient a therapeutically effective amount of at least one anti-convulsant. Examples of the pain treatable are described above.

In general the compounds of this invention used to treat pain will have CXCR2 antagonistic activity.

NSAIDs are well known to those skilled in the art and can be used in their known dosages and dosage regimens. Examples of NSAIDs include but are not limited to piroxicam, ketoprofen, naproxen, indomethacin, and ibuprofen

COXIB inhibitors are well known to those skilled in the art and can be used in their known dosages and dosage regimens. Examples of COXIB inhibitors include but are not limited to: rofecoxib and celecoxib.

Anti-depressants are well known to those skilled in the art and can be used in their known dosages and dosage regimens. Examples of anti-depressants include but are not limited to amitriptyline and nortriptyline.

Anti-convulsants are well known to those skilled in the ad and can be used in their known dosages and dosage regimens. Examples of Anticonvulsants include but are not limited to: gabapentin, carbamazepine, pregabalin, and lamotragine.

Another embodiment of this invention is directed to a method of treating Kaposi's sarcoma, melanoma, gastric carcinoma, and non-small cell carcinoma in a patient in need of such treatment comprising administering to said patient an effective amount of at least one (e.g., 1-3, usually 1) compound of formula IA, or a pharmaceutically acceptable salt thereof.

Another embodiment of this invention is directed to a meth of treating melanoma, gastric carcinoma, and non-small cell carcinoma in a patient in need of such treatment comprising administering to said patient an effective amount of at least one (e.g., 1-3, usually 1) compound of formula IA, or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is directed to a method of treating cancer in a patient (e.g., a mammal, such as a human being) in need of such treatment, comprising administering to said patient, concurrently or sequentially, a therapeutically effective amount of (a) at least one (e.g., 1-3, and usually one) compound of formula IA, or a pharmaceutically acceptable salt thereof, and (b) at least one (e.g., 1, 2 or 3) anticancer agent selected from the group consisting of: (1) microtubule affecting agents, (2) antineoplastic agents, (3) anti-angiogenesis agents, (4) VEGF receptor kinase inhibitors, (5) antibodies against the VEGF receptor, (6) interferon, and (7) radiation.

In further embodiments of this invention that are directed to the treatment of cancer, at least one (e.g., 1-3, and usually one) compound of formula IA, or a pharmaceutically acceptable salt thereof is administered in combination with at least one (e.g., 1 or 2, or 1) antineoplastic agent selected from the group consisting of: gemcitabine, paclitaxel (Taxol®), 5-Fluorouracil (5-FU), cyclophosphamide (Cytoxan®), temozolomide, taxotere and Vincristine.

In another embodiment the present invention provides a method of treating cancer in a patient (e.g., a mammal, such as a human being) in need of such treatment, comprising administering, concurrently or sequentially, an effective amount of (a) at least one (e.g., 1-3, usually 1) compound of formula IA, or a pharmaceutically acceptable salt thereof, and (b) at least one (e.g., 1-3, usually 1) microtubule affecting agent (e.g., paclitaxel).

In the method of treating a pulmonary disease (e.g., COPD, asthma, or cystic fibrosis), at least one (usually 1) compound of formula IA, or a pharmaceutically acceptable salt thereof, is administered in combination with at least one compound selected from the group consisting of: glucocorticoids, 5-lipoxygenase inhibitors, β-2 adrenoceptor agonists, muscarinic M1 antagonists, muscarinic M3 antagonists, muscarinic M2 agonists, NK3 antagonists, LTB4 antagonists, cysteinyl leukotriene antagonists, bronchodilators, PDE4 inhibitors, PDE inhibitors, elastase inhibitors, MMP inhibitors, phospholipase A2 inhibitors, phospholipase D) inhibitors, histamine H1 antagonists, histamine H3 antagonists, dopamine agonists, adenosine 42 agonists, NK1 and NK2 antagonists, GABA-b agonists, nociceptin agonists, expectorants, mucolytic agents, decongestants, antioxidants, anti-IL-8 anti-bodies, anti-IL-5 antibodies, anti-IgE antibodies, anti-TNF antibodies, IL-10, adhesion molecule inhibitors, and growth hormones. Agents that belong to these classes include, but are not limited to, beclomethasone, mometasone, ciclesonide, budesonide, fluticasone, albuterol, salmeterol, formoterol, loratadine, desloratadine, tiotropium bromide, MSI-ipratropium bromide, montelukast, theophilline, cilomilast, roflumilast cromolyn, ZD-4407, talnetant, LTB-019, revatropate, pumafentrine, CP-955, AR-C-89855, BAY-19-8004, GW-328267, QAB-149, DNK-333, YM-40461 and TH-9506 or pharmaceutically acceptable formulations thereof.

Representative embodiments of the novel compounds of this invention are described below. The embodiments have been numbered for purposes of reference thereto.

Embodiment No. 1 is directed to the novel compounds of formula IA wherein B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 2 is directed to the novel compounds of formula IA wherein B is:

and all other substitutents are as defined for of formula IA,

Embodiment No. 3 is directed to the novel compounds of formula IA wherein B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 4 is directed to the novel compounds of formula IA wherein B is,

and all other substitutents are as defined for of formula IA.

Embodiment No. 5 is directed to the novel compounds of formula IA wherein B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 6 is directed to the novel compounds of formula IA wherein B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 7 is directed to the novel compounds of formula IA wherein B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 8 is directed to the novel compounds of formula IA wherein B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 9 is directed to the novel compounds of formula IA wherein B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 10 is directed to the novel compounds of formula IA wherein B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 11 is directed to the novel compounds of formula IA wherein B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 12 is directed to the novel compounds of formula IA wherein B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 13 is directed to the novel compounds of formula IA wherein to B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 14 is directed to the novel compounds of formula IA wherein B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 15 is directed to the novel compounds of formula IA wherein B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 16 is directed to the novel compounds of formula IA wherein B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 17 is directed to the novel compounds of formula IA wherein B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 18 is directed to the novel compounds of formula IA wherein B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 19 is directed to compounds of formula A wherein B is selected from the group consisting of:

and R³ for this B group is selected from the group consisting of: C(O)NR¹³R¹⁴,

and all other substituents are as defined for formula IA.

Embodiment No. 20 is directed to compounds of formula IA wherein B is:

and all other substituents are as defined in formula IA.

Embodiment No. 21 is directed to compounds of formula IA wherein B is

R¹³ and R¹⁴ are independently selected from the group consisting of H and alkyl (e.g., methyl, ethyl, isopropyl and t-butyl), and all other substituents are as defined in formula IA.

Embodiment No. 22 is directed to compounds of formula IA wherein B is

wherein:

-   -   (1) R² is —OH and all other substituents are as defined in         formula IA, or     -   (2) R² is —OH, and R¹³ and R¹⁴ are independently selected from         the group, consisting of: H and alkyl (e.g., methyl, ethyl,         isopropyl and t-butyl), or     -   (3) R² is —OH, and R¹³ and R¹⁴ are the same or different and         alkyl group (e.g., methyl, ethyl, isopropyl and t-butyl), for         example the same alkyl group, for example methyl, and     -   (4) and all other substituents are as defined in formula IA.

Embodiment No. 23 is directed to compounds of formula IA wherein B is

R³ is selected from the group consisting of,

and all other substituents are as defined in formula IA.

Embodiment No. 24 is directed to compounds of formula IA wherein B is

R³ is selected from the group consisting of:

R² is —OH, and all other substituents are as defined in formula IA.

Embodiment No. 25 is directed to compounds of formula IA wherein B is:

and all other substituents are as defined in formula IA.

Embodiment No. 26 is directed to compounds of formula IA wherein B is,

R² is —OH, and all other substituents are as defined in formula IA.

Embodiment No. 27 is directed to compounds of formula IA wherein B is:

R² is as defined for compounds of formula IA, R¹³ and R¹⁴ are independently selected from the group consisting of H and alkyl (e.g., methyl, ethyl, isopropyl and t-butyl), and all other substituents areas defined for compounds of formula IA. For example, R¹³ and R¹⁴ are the same or different alkyl group. Also, for example, R¹³ and R¹⁴ are the same alkyl group. Also, for example, R¹³ and R¹⁴ are methyl.

Embodiment No. 28 is directed to the novel compounds of formula IA wherein B is:

R² is —OH, R¹³ and R¹⁴ are independently selected from the group consisting of H and alkyl (e.g., methyl, ethyl, isopropyl and t-butyl), and all other substituents areas defined for compounds of formula IA. For example, R¹³ and R¹⁴ are the same or different alkyl group. Also, for example, R¹³ and R¹⁴ are the same alkyl group. Also, for example, R¹³ and R¹⁴ are methyl.

Embodiment No. 29 is directed to novel compounds of formula IA wherein B is as described in Embodiment No. 23, R⁴ is H, R⁵ is H, R⁶ is H, and all other substituents are as defined for compounds of formula IA.

Embodiment No. 30 is directed to novel compounds of formula IA wherein B is as described in Embodiment No. 24, R¹⁴ is H, R⁵ is H, R⁶ is H, and all other substituents areas defined for compounds of formula IA.

Embodiment No. 31 is directed to novel compounds of formula IA wherein B is as described in Embodiments Nos. 21, 22, 25 and 26, except that R¹³ and R¹⁴ are each methyl, and all other substituents are as defined in formula IA.

Embodiment No. 32 is directed to compounds of formula IA wherein B is:

R¹¹ is H or methyl (preferably H), and all other substituents are as defined in formula IA.

Embodiment No. 33 is directed to compounds of formula IA wherein B is:

R² is —OH, and all other substituents are as defined in formula IA.

Embodiment No. 34 is directed to compounds of formula IA wherein B is:

R³ is —C(O)NR¹³R¹¹ and all other substituents are as defined in formula IA.

Embodiment No. 35 is directed to compounds of formula IA wherein B is:

R³ is —S(O)_(t)NR¹³R¹⁴ (e.g., t is 2), and all other substituents are as defined in formula IA.

Embodiment No. 36 is directed to compounds of formula IA wherein B is:

R² is —OH, R³ is —C(O)NR¹³R¹⁴, and all other substituents are as defined in formula IA.

Embodiment No. 37 of this invention is directed to compounds of formula IA wherein B is:

R² is —OH, and R³ is —S(O)_(t)NR¹³R¹⁴ (e.g., t is 2), and all other substituents are as defined in formula IA.

Embodiment No. 38 is directed to compounds of formula IA wherein B is:

R² is —OH, R³ is —C(O)NR¹³R¹⁴, R¹¹ is H or methyl (preferably H), and all other substituents are as defined in formula IA.

Embodiment No. 39 is directed to compounds of formula IA wherein B is:

R² is —OH, R³ is —S(O)_(t)NR¹³R¹⁴ (e.g., t is 2), R¹¹ is H or methyl (preferably H), and all other substituents are as defined in formula IA

Embodiment No. 40 is directed to compounds of formula IA wherein B is:

R² is —OH, R³ is —C(O)NR¹³R¹⁴, R¹¹ is H or methyl (preferably H), and R¹³ and R¹⁴ are independently selected from the group consisting of: H, alkyl (e.g., methyl, ethyl, isopropyl and t-butyl), unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heteroaryl and substituted heteroaryl, and all other substituents are as defined in formula IA. For example, one of R¹³ or R¹⁴ is alkyl (e.g., methyl). An example of a substituted heteroaryl group is

Embodiment No. 41 is directed to compounds of formula IA wherein B is:

R² is —OH, R³ is —S(O)_(t)NR¹³R¹⁴ (e.g., t is 2), R¹¹ is H or methyl (preferably H), and R¹³ and R¹⁴ are independently selected from the group consisting of: H, alkyl (e.g., methyl, ethyl, isopropyl, and t-butyl), unsubstituted cycloalkyl, and substituted cycloalkyl, and all other substituents are as defined in formula IA. For example R³ is (1) —SO₂NH₂ or (2) —SO₂NR¹³R¹⁴ wherein R¹³ and R¹⁴ are the same or different alkyl group (e.g., methyl, ethyl, isopropyl and t-butyl), e.g., the same alkyl group, such as, for example —SO₂N(CH₃)₂.

Embodiment No. 42 is directed to compounds of formula IA wherein B is:

R¹¹ is H, and all other substituents are as defined in formula IA.

Embodiment No. 43 is directed to compounds of formula IA wherein B is:

R² is —OH, and all other substituents are as defined in formula IA.

Embodiment No. 44 is directed to compounds of formula IA wherein B is:

R³ is —C(O)NR¹³R¹⁴, and all other substituents are as defined in formula IA.

Embodiment No. 45 is directed to compounds of formula IA wherein B is:

R³ is —S(O)_(t)NR¹³R¹⁴ (e.g., t is 2), and all other substituents are as defined in formula IA.

Embodiment No. 46 is directed to compounds of formula IA wherein B is:

R² is —OH, R³ is —C(O)NR¹³R¹⁴ and all other substituents are as defined in formula IA.

Embodiment No. 47 of this invention is directed to compounds of formula IA wherein B is:

R² is —OH, and R³ is —S(O)_(t)NR¹³R¹⁴ (e.g., t is 2), and all other substituents are as defined in formula IA.

Embodiment No. 48 is directed to compounds of formula IA wherein B is:

R² is —OH, R³ is —C(O)NR¹³R¹⁴, R¹¹ is H, and all other substituents are as defined in formula IA.

Embodiment No. 49 is directed to compounds of formula IA wherein B is:

R² is —OH, R³ is —S(O)NR¹³R¹⁴ (e.g., t is 2), R¹¹ is H, and all other substituents are as defined in formula IA.

Embodiment No. 50 is directed to compounds of formula IA wherein B is:

R² is —OH, R³ is —C(O)NR¹³R¹⁴, R¹¹ is H, and R¹³ and R¹⁴ are independently selected from the group consisting of: alkyl, unsubstituted heteroaryl and substituted heteroaryl, and all other substituents are as defined in formula IA. For example, one of R¹³ or R¹⁴ is alkyl (e.g., methyl). An example of a substituted heteroaryl group is

Embodiment No. 51 is directed to compounds of formula IA wherein B is:

R² is —OH, R³ is —S(O)_(t)NR¹³R¹⁴ (e.g., t is 2), R¹¹ is H, R¹³ and R¹⁴ are independently selected from the group consisting of: H and alkyl (e.g., methyl, ethyl, isopropyl, and t-butyl), and all other substituents are as defined in formula IA. For example R³ is (1) —SO₂NH₂ and (2) —SO₂NR¹³R¹⁴ wherein R¹³ and R¹⁴ are the same or different alkyl group (e.g., methyl, ethyl, isopropyl and t-butyl), e.g., the same alkyl group, such as, for example —SO₂N(CH₃)₂.

Embodiment No. 52 is directed to compounds of formula IA wherein substituent B is selected from the group consisting of,

wherein R² to R⁶ and R¹⁰ to R¹⁴ are as defined above for the compounds of formula IA.

Embodiment No. 53 is directed to compounds of formula IA wherein substituent B in formula is selected from the group consisting of:

wherein

R² is selected from the group consisting of, H, OH, —NHC(O)R¹³ or and —NHSO₂R¹³;

R³ is selected from the group consisting of: —SO₂NR¹³R¹⁴, —NO₂, cyano, —C(O)NR¹³R¹⁴, —SO₂R¹³; and —C(O)R¹³;

R⁴ is selected from the group consisting of: H, —NO₂, cyano, —CH₃, halogen, and —CF₃;

R⁵ is selected from the group consisting of: H, —CF₃, —NO₂, halogen and cyano;

R⁶ is selected from the group consisting of: H, alkyl and —CF₃;

each R¹⁰ and R¹¹ is independently selected from the group consisting of: R¹³, hydrogen, halogen, —CF₃, —NR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —C(O)R¹³, —SH, —SO_((t))NR¹³R¹⁴, —SO₂R¹³, —NHC(O)R¹³, —NHSO₂NR¹³R¹⁴, —NHSO₂R¹³, —C(O)NR¹³R¹⁴, —C(O)NR¹³OR¹⁴, —OC(O)R¹³, —COR¹³, —OR³, and cyano;

each R¹³ and R¹⁴ is independently selected from the group consisting of: H, methyl, ethyl and isopropyl; or

R¹³ and R¹⁴ when taken together with the nitrogen they are attached to in the groups —NR¹³R¹⁴, —C(O)NR¹³R¹⁴, —SO₂NR¹³R¹⁴, —OC(O)NR¹³R¹⁴, —CONR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —SO_(t)NR¹³R¹⁴, —NHSO₂NR¹³R¹⁴ form an unsubstituted or substituted saturated heterocyclic ring (preferably a 3 to 7 membered ring) optionally having one additional heteroatom selected from the group consisting of: O, S or NR¹⁸; wherein R¹⁸ is selected from the group consisting of: H, alkyl, aryl, heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹ and —C(O)NR¹⁹R²⁰; wherein each R¹⁹ and R²⁰ is independently selected from the group consisting of: alkyl, aryl and heteroaryl: wherein there are 1 to 3 substituents on the substituted cyclized R¹³ and R¹⁴ groups (i.e., the substituents on the ring formed when R¹³ and R¹⁴ are taken together with the nitrogen to which they are bound) and each substituent is independently selected from the group consisting of, alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, —C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵ provided that R¹⁵ is not H, —NHC(O)NR¹⁵R¹⁶ and halogen; and wherein each R¹⁵ and R¹⁶ is independently selected from the group consisting: of H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl.

Embodiment No. 54 is directed to compounds of formula A wherein substituent B in formula selected from the group consisting of:

wherein:

R² is selected from the group consisting of: H, OH, —NHC(O)R¹³ and —NHSO₂R¹³;

R³ is selected from the group consisting of: —C(O)NR¹³R¹⁴, —SO₂NR¹³R¹⁴, —NO₂, cyano, —SO₂R¹³; and —C(O)OR¹³;

R⁴ is selected from the group consisting of: H, —NO₂, cyano, —CH₃ or —CF₃;

R⁵ is selected from the group consisting of: H, —CF₃, —NO₂, halogen and cyano; and

R⁶ is selected from the group consisting of: H, alkyl and —CF₃;

R¹¹ is selected from the group consisting of: H, halogen and alkyl; and

each R¹³ and R¹⁴ is independently selected from the group consisting of: H, methyl, ethyl and isopropyl; or

R¹³ and R¹⁴ when taken together with the nitrogen they are attached to in the groups —NR¹³R¹⁴, —C(O)NR¹³R¹⁴, —SO₂NR¹³R¹⁴, —OC(O)NR¹³R¹⁴, —CONR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —SO_(t)NR¹³R¹⁴, —NHSO₂NR¹³R¹⁴ form an unsubstituted or substituted saturated heterocyclic ring (preferably a 3 to 7 membered ring) optionally having one additional heteroatom selected from O, S or NR¹⁸ wherein R¹⁸ is selected from H, alkyl, aryl, heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹ and —C(O)NR¹⁹R²⁰, wherein each R¹⁹ and R²⁰ is independently selected from alkyl, aryl and heteroaryl, wherein there are 1 to 3 substituents on the substituted cyclized R¹³ and R¹⁴ groups (i.e., on the ring formed when R¹³ and R¹⁴ are taken together with the nitrogen to which they are bound) and each substituent is independently selected from the group consisting of: alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, —C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵ provided that R¹⁵ is not H, —NHC(O)NR¹⁵R¹⁶ and halogen; and wherein each R¹⁵ and R¹⁶ is independently selected from the group consisting of: H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl.

Embodiment No. 55 is directed to compounds of formula IA wherein substituent B is selected from the group consisting of:

wherein:

R² is selected from the group consisting of: H, OH, —NHC(O)R¹³ and —NHSO₂R¹³;

R³ is selected from the group consisting of: —C(O)NR¹³R¹⁴—SO₂NR¹³R¹⁴, —NO₂N cyano, and —SO₂R¹³;

R⁴ is selected from the group consisting of: H, —NO₂, cyano, —CH₃ or —CF₃;

R⁵ is selected from the group consisting of: H, —CF₃, —NO₂, halogen and cyano; and

R⁶ is selected from the group consisting of: H, alkyl and —CF₃;

R¹¹ is selected from the group consisting of: H, halogen and alkyl; and

each R¹³ and R¹⁴ is independently selected from the group consisting of: H, methyl and ethyl.

Embodiment No. 56 is directed to compounds of formula IA wherein substituent B is selected from the group consisting of:

wherein:

R² is —OH;

R³ is selected from the group consisting of —SO₂NR¹³R¹⁴ and —CONR¹³R¹⁴;

R⁴ is selected form the group consisting of: H, —CH₃ and —CF₃;

R⁵ is selected from the group consisting of: H and cyano;

R⁶ is selected from the group consisting of: H, —CH₃ and —CF₃;

R¹¹ is H; and

R¹³ and R¹⁴ are independently selected from the group consisting of H and methyl (e.g., for —SO₂NR¹³R¹⁴ both R¹³ and R¹⁴ are H, or both R¹³ and R¹⁴ are methyl, also, for example, for —CONR¹³R¹⁴ both R¹³ and R¹⁴ are methyl).

Embodiment No. 57 is directed to compounds of formula IA wherein substituent B is selected from the group consisting of:

wherein all substituents are as defined for formula IA.

Embodiment No. 58 is directed to compounds of formula IA wherein substituent B is selected from the group consisting of:

Embodiment No. 59 is directed to compounds of formula IA wherein substituent B is selected from the group consisting of:

Embodiment No. 60 is directed to compounds of formula IA wherein substituent B is selected from the group consisting of:

Embodiment No. 61 is directed to compounds of formula IA wherein substituent B is selected from the group consisting of:

Embodiment No. 62 is directed to compounds of formula IA wherein substituent B is:

Embodiment No. 63 is directed to compounds of formula IA wherein substituent B is:

Embodiment No. 64 is directed to compounds of formula IA wherein substituent B is:

Embodiment No. 65 is directed to compounds of formula IA wherein: substituent A is selected from the group consisting of:

wherein the above rings are unsubstituted or substituted, as described for formula IA: and

wherein in (a) and (b): each R⁷ and R⁸ is independently selected from the group consisting of: H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, —CO₂R¹³, —CONR¹³R¹⁴, fluoroalkyl, alkynyl, alkenyl, and cycloalkenyl, wherein said substituents on said R⁷ and R⁸ substituted groups are selected from the group consisting of: a) cyano, b) —CO₂R¹³, c) —C(O)NR¹³R¹⁴, d) —SO₂NR¹³R¹⁴, e) —NO₂, f) —CF₃, g) —OR¹³, h) —NR¹³R¹⁴, i) —OC(O)R¹³, j) —OC(O)NR¹³R¹⁴, and k) halogen; and R^(8a) and R⁹ are as defined in formula IA.

Embodiment No. 66 is directed to compounds of formula IA wherein substituent A is selected from the group consisting of:

wherein the above rings are unsubstituted, or the above rings are substituted with 1 to 3 substituents independently selected from the group consisting of: halogen, alkyl, cycloalkyl, —CF₃, cyano, —OCH₃, and —NO₂; each R⁷ and R⁸ is independently selected from the group consisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl (such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g., cyclopropyl, and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); and R⁹ is selected from the group consisting of: H, halogen, alkyl, cycloalkyl, —CF₃, cyano, —OCH₃, and —NO₂; and

wherein each R⁷ and R⁸ is independently selected from the group consisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl (such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g., cyclopropyl, and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); wherein R^(8a) is as defined in formula IA, and wherein R⁹ is selected from the group consisting of: H, halogen, alkyl, cycloalkyl, —CF₃, cyano, —OCH₃, and —NO₂; each R⁷ and R⁸ is independently selected from the group consisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl (such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g., cyclopropyl, and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl).

Embodiment No. 67 is directed to the novel compounds of formula IA wherein substituent A is selected from the group consisting of:

wherein the above rings are unsubstituted, or the above rings are substituted with 1 to 3 substituents independently selected from the group consisting of: H, F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ is selected from the group consisting of: H, fluoroalkyl, alkyl and cycloalkyl; R⁸ is selected form the group consisting of: H, alkyl, —CF₂CH₃ and —CF₃; and R⁹ is selected from the group consisting of: H, F, Cl, Br, alkyl or —CF₃; and

wherein R⁷ is selected from the group consisting of: H, fluoroalkyl, alkyl and cycloalkyl; R⁸ is selected form the group consisting of: H, alkyl, —CF₂CH₃ and —CF₃; and R^(8a) is as defined for formula IA.

Embodiment No. 68 is directed to compounds of formula IA wherein substituent A is selected from the group consisting of:

wherein the above rings are unsubstituted, or the above rings are substituted with 1 to 3 substituents independently selected from the group consisting of: H, F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ is selected from the group consisting of: H, —CF₃, —CF₂CH₃, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and

wherein R⁷ is selected from the group consisting of: H, —CF₃, —CF₂CH₃, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and R^(8a) is as defined for formula IA.

Embodiment No. 69 is directed compounds of formula IA wherein substituent A is selected from the group consisting of:

wherein the above rings are unsubstituted, or the above rings are substituted with 1 to 3 substituents independently selected from the group consisting of, F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ is selected from the group consisting of: H, —CF₃, —CF₂CH₃, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and

wherein R⁷ is selected from the group consisting of: H, —CF₃, —CF₂CH₃, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and R^(8a) is as defined for formula IA;

Embodiment No. 70 is directed compounds of formula IA wherein substituent A is selected from the group consisting of:

wherein all substitutents are as defined for formula IA.

Embodiment No. 71 is directed to compounds of formula IA wherein substituent A is selected from the group consisting of:

Embodiment No. 72 is directed to compounds of formula IA wherein substituent A is selected from the group consisting of:

Embodiment No. 73 is directed to compounds of formula IA wherein substituent A is selected from the group consisting of:

Embodiment No. 74 is directed to compounds of formula IA wherein substituent A is selected from the group consisting of:

Embodiment No. 75 is directed to compounds of formula IA wherein substituent A is selected from the group consisting of:

Embodiment No. 76 is directed to compounds of formula IA wherein substituent A is:

Embodiment No. 77 is directed to compounds of formula IA wherein substituent A is:

Embodiment No. 78 is directed to compounds of formula IA wherein substituent A is:

Embodiment No. 79 is directed to compounds of formula IA wherein substituent A is:

Embodiment No. 80 is directed to compounds of formula IA wherein substituent A is selected from the group consisting of:

and substituent B is selected from the group consisting of:

Embodiment No. 81 is directed to compounds of formula IA wherein substituent A is selected from the group consisting of:

and substituent B is selected from the group consisting of:

Embodiment No. 82 is directed to novel compounds of formula IA wherein B is as described in any one of the Embodiment Nos. 1 to 64, and A is as defined in any one of the Embodiment Nos. 65 to 79.

Embodiment No. 83 is directed to compounds of formula IA wherein B is as described in any one of the Embodiment Nos. 1 to 64, and A is:

and all other substituents are as defined for formula IA.

Embodiment No. 84 is directed to compounds of formula IA wherein B is as described in any one of the Embodiment Nos. 1 to 64, and A is:

wherein R⁷ is H, and R⁸ is alkyl (e.g., methyl, ethyl, isopropyl, cyclopropyl and t-butyl), and all other substituents are as defined for formula IA.

Embodiment No. 85 is directed to compounds of formula IA wherein B is as described in any one of the Embodiment Nos. 1 to 64, and A is:

and all other substituents are as defined for formula IA.

Embodiment No. 86 is directed to compounds of formula IA wherein B is as described in any one of the Embodiment Nos. 1 to 64, and A is:

wherein the furan ring is unsubstituted or substituted as described in the definition of A for formula IA, and all other substituents are as defined for formula IA.

Embodiment No. 87 is directed to compounds of formula IA wherein B is described in any one of the Embodiment Nos. 1 to 64, and A is

wherein the furan ring is substituted and all other substituents are as defined for formula IA.

Embodiment No. 88 is directed to compounds of formula IA wherein B is as described in any one of the Embodiment Nos. 1 to 64, and A is

wherein the furan ring is substituted with at least one (e.g., 1 to 3, or 1 to 2) alkyl group and all other substituents are as defined for formula IA.

Embodiment No. 89 is directed to compounds of formula IA wherein B is as described in any one of the Embodiment Nos. 1 to 64, A is

wherein the furan ring is substituted with one alkyl group and all other substituents are as defined for formula IA.

Embodiment No. 90 is directed to compounds of formula IA wherein B is as described in any one of the Embodiment Nos. 1 to 64, and A is

wherein the furan ring is substituted with one C₁ to C₃ alkyl group (e.g., methyl or isopropyl), and all other substituents are as defined for formula IA.

Embodiment No. 91 is directed to novel compounds of formula IA wherein B is as described in any one of the Embodiment Nos. 1 to 64, and A is as defined in any one of the Embodiment Nos. 86 to 90, except that R⁷ and R⁸ are the same or different and each is selected from the group consisting of: H and alkyl.

Embodiment No. 92 is directed to novel compounds of formula IA wherein B is as described in any one of the Embodiment Nos. 1 to 64, and A is as defined in any one of the Embodiment Nos. 86 to 90, except that R⁷ is H, and R⁸ is alkyl (e.g., ethyl or t-butyl).

Embodiment No. 93 is directed to compounds of formula IA wherein:

-   -   (1) substituent A in formula IA is selected from the group         consisting of:

wherein the above rings are unsubstituted or substituted, as described for formula IA: and

wherein in (a) and (b) above, each R⁷ and R⁸ is independently selected from the group consisting of: H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, —CO₂R¹³, —CONR¹³R¹⁴, fluoroalkyl, alkynyl, alkenyl, and cycloalkenyl, wherein said substituents on said R⁷ and R⁸ substituted groups are selected from the group consisting of, a) cyano, b) —CO₂R¹³, c) —C(O)NR¹³R¹⁴, d) —SO₂NR¹³R¹⁴, e) —NO₂, f) —CF₃, g) —OR¹³, h) —NR¹³R¹⁴, i) —OC(O)R¹³, j) —OC(O)NR¹³R¹⁴ and k) halogen; and R^(8a) and R⁹ are as defined in formula IA; and

-   -   (2) substituent B in formula IA is selected from the group         consisting of:

wherein R² to R⁶ and R¹⁰ to R¹⁴ are as defined above for the novel compounds of formula IA.

Embodiment No. 94 is directed to compounds of formula IA wherein:

-   -   (1) substituent A in formula IA is selected from the group         consisting of:

wherein the above rings are unsubstituted, or the above rings are substituted with 1 to 3 substituents independently selected from the group consisting of: halogen, alkyl, cycloalkyl, —CF₃, cyano, —OCH₃, and —NO₂; each R⁷ and R⁸ is independently selected from the group consisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl (such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g., cyclopropyl, and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); and R⁹ is selected from the group consisting of: —H, halogen, alkyl, cycloalkyl, —CF₃, cyano, —OCH₃, and —NO₂; and

wherein each R⁷ and R⁸ is independently selected from the group consisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl (such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g., cyclopropyl, and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); wherein R^(8a) is as defined in formula IA, and wherein R⁹ is selected from the group consisting of: H, halogen, alkyl, cycloalkyl, —CF₃, cyano, —OCH₃, and —NO₂; each R⁷ and R⁸ is independently selected from the group consisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl (such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g., cyclopropyl, and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); and

-   -   (2) substituent B in formula IA is selected from the group         consisting of:

wherein

R² is selected from the group consisting of: H, OH, —NHC(O)R¹³ or and —NHSO₂R¹³;

R³ is selected from the group consisting of: —SO₂NR¹³R¹⁴, —NO₂, cyano, —C(O)NR¹³R¹⁴, —SO₂R¹³; and —C(O)OR¹³;

R⁴ is selected from the group consisting of: H, —NO₂, cyano, —CH₃, halogen, and —CF₃;

R⁵ is selected from the group consisting of: H, —CF₃, —NO₂, halogen and cyano;

R⁶ is selected from the group consisting of: H, alkyl and —CF₃;

each R¹⁰ and R¹¹ is independently selected from the group consisting of: R¹³, hydrogen, halogen, —CF₃, —NR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —C(O)OR¹³, —SH, —SO_((t))NR¹³R¹⁴, —SO₂R¹³, —NHC(O)R¹³, —NHSO₂NR¹³R¹⁴, —NHSO₂R¹³, —C(O)NR¹³R¹⁴, —C(O)NR¹³OR⁴, —OC(O)R¹³, —COR¹³, —OR¹³ and cyano;

each R¹³ and R¹⁴ is independently selected from the group consisting of: H, methyl, ethyl and isopropyl; or

R¹³ and R¹⁴ when taken together with the nitrogen they are attached to in the groups —NR¹³R¹⁴, —C(O)NR¹³R¹⁴, —SO₂NR³R⁴, —OC(O)NR¹³R¹⁴, —CONR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —SO_(t)NR¹³R¹⁴, —NHSO₂NR¹³R¹⁴ form an unsubstituted or substituted saturated heterocyclic ring (preferably a 3 to 7 membered ring) optionally having one additional heteroatom selected from the group consisting of: O, S or NR¹⁸; wherein R¹⁸ is selected from the group consisting of: H, alkyl, aryl, heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹ and —C(O)NR¹⁹R²⁰; wherein each R¹⁹ and R²⁰ is independently selected from the group consisting of: alkyl, aryl and heteroaryl; wherein there are 1 to 3 substituents on the substituted cyclized R¹³ and R¹⁴ groups (i.e., the substituents on the ring formed when R¹³ and R¹⁴ are taken together with the nitrogen to which they are bound) and each substituent is independently selected from the group consisting of: alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, —C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵ provided that R¹⁵ is not H, —NHC(O)NR¹⁵R¹⁶ and halogen; and wherein each R¹⁵ and R¹⁶ is independently selected from the group consisting: of H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl.

Embodiment No. 95 is directed to compounds of formula IA wherein substituent A in formula IA is even more preferably selected from the group consisting of:

wherein the above rings are unsubstituted, or the above rings are substituted with 1 to 3 substituents independently selected from the group consisting of: H, F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ is selected from the group consisting of: H, fluoroalkyl, alkyl and cycloalkyl; R⁸ is selected form the group consisting of: H, alkyl, —CF₂CH₃ and —CF₃; and R⁹ is selected from the group consisting of: H, F, Cl, Br, alkyl or —CF₃; and

wherein R⁷ is selected from the group consisting of: H, fluoroalkyl, alkyl and cycloalkyl; R⁸ is selected form the group consisting of: H, alkyl, —CF₂CH₃ and —CF₃; and R^(8a) is as defined for formula IA.

Embodiment No. 96 is directed to compounds of formula IA wherein:

-   -   (1) substituent A in formula IA is selected from the group         consisting of:

wherein the above rings are unsubstituted, or the above rings are substituted with 1 to 3 substituents independently selected from the group consisting of: H, F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ is selected from the group consisting of: H, —CF₃, —CF₂CH₃, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and

wherein R⁷ is selected from the group consisting of: H, —CF₃, —CF₂CH₃, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and R^(8a) is as defined for formula IA.

-   -   (2) substituent B in formula IA is selected from the group         consisting of:

wherein:

R² is selected from the group consisting of: H, OH, —NHC(O)R¹³ and —NHSO₂R¹³,

R³ is selected from the group consisting of: —C(O)NR¹³R¹⁴, —SO₂NR¹³R¹⁴, —NO₂, cyano, —SO₂R¹³; and —C(O)OR¹³;

R⁴ is selected from the group consisting of: H, —NO₂, cyano, alkyl (e.g., —CH₃ and ethyl), —CF₃, and halogen;

R⁵ is selected from the group consisting of: H, —CF₃, —NO₂, halogen and cyano; and

R⁶ is selected from the group consisting of: H, alkyl and —CF₃;

R¹¹ is selected from the group consisting of: H, halogen and alkyl; and

each R¹³ and R¹⁴ is independently selected from the group consisting of: H, methyl, ethyl and isopropyl; or

R¹³ and R¹⁴ when taken together with the nitrogen they are attached to in the groups —NR¹³R¹⁴, —C(O)NR¹³R¹⁴, —SO₂NR¹³R¹⁴, —OC(O)NR¹³R¹⁴, —CONR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —SO_(t)NR¹³R¹⁴, —NHSO₂NR¹³R¹⁴ form an unsubstituted or substituted saturated heterocyclic ring (preferably a 3 to 7 membered ring) optionally having one additional heteroatom selected from O, S or NR¹⁸ wherein R¹⁸ is selected from H, alkyl, aryl, heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹ and —C(O)NR¹⁹R²⁰, wherein each 19 and R²⁰ is independently selected from alkyl, aryl and heteroaryl, wherein there are 1 to 3 substituents on the substituted cyclized R¹³ and R¹⁴ groups (i.e., on the ring formed when R¹³ and R¹⁴ are taken together with the nitrogen to which they are bound) and each substituent is independently selected from the group consisting of: alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, —C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵ provided that R¹⁵ is not H, —NHC(O)NR¹⁵R¹⁶ and halogen; and wherein each R¹⁵ and R¹⁶ is independently selected from the group consisting of: H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl.

Embodiment No. 97 is directed to compounds of formula IA wherein:

-   -   (1) substituent A in formula IA is selected from the group         consisting of:

wherein the above rings are unsubstituted, or the above rings are substituted with 1 to 3 substituents independently selected from the group consisting of: F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ is selected from the group consisting of: H, —CF₃, —CF₂CH₃, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and

wherein R⁷ is selected from the group consisting of: H, —CF₃, —CF₂CH₃, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and R^(8a) is as defined for formula IA;

-   -   (2) substituent B in formula IA is selected from the group         consisting of:

wherein:

R² is selected from the group consisting of: H, OH, —NHC(O)R¹³ and —NHSO₂R¹³;

R³ is selected from the group consisting of: —C(O)NR¹³R¹⁴, —SO₂NR¹³R¹⁴, —NO₂, cyano, and —SO₂R¹³;

R⁴ is selected from the group consisting of: H, —NO₂, cyano, alkyl (e.g., —CH₃ and ethyl), —CF₃ and halogen;

R⁵ is selected from the group consisting of: H, —CF₃, —NO₂, halogen and cyano; and

R⁶ is selected from the group consisting of: H, alkyl and —CF₃;

R¹¹ is selected from the group consisting of: H, halogen and alkyl; and

each R¹³ and R¹⁴ is independently selected from the group consisting of: H and unsubstituted alkyl (e.g., methyl and ethyl).

Embodiment No. 98 is directed to compounds of formula IA wherein:

-   -   (1) substituent A in formula IA is selected from the group         consisting of:

-   -   (2) substituent B in formula IA is selected from the group         consisting of:

wherein:

R² is —OH;

R³ is selected from the group consisting of: —SO₂NR¹³R¹⁴ and —CONR¹³R¹⁴;

R⁴ is selected form the group consisting of: H, Br, —CH₃, ethyl and —CF₃;

R⁵ is selected from the group consisting of, H and cyano;

R⁶ is selected from the group consisting of: H, —CH₃ and —CF₃;

R¹¹ is H; and

R¹³ and R¹⁴ are independently selected from the group consisting of H and methyl (e.g., for —SO₂NR¹³R¹⁴ both R¹³ and R¹⁴ are H, or both R¹³ and R¹⁴ are methyl, also, for example, for —CONR¹³R¹⁴ both R¹³ and R¹⁴ are methyl).

Embodiment No. 99 is directed to compounds of formula IA wherein substituent A is as defined in Embodiment No. 70 and substituent B is as defined in Embodiment No. 57.

Embodiment No. 100 is directed to compounds of formula IA wherein substituent A is as defined in Embodiment No. 70 and substituent B is as defined in Embodiment No. 58.

Embodiment No. 101 is directed to compounds of formula IA wherein substituent A is as defined in Embodiment No. 70 and substituent B is as defined in Embodiment No. 59.

Embodiment No. 102 is directed to compounds of formula IA wherein substituent A is as defined in Embodiment No. 71 and substituent B is as defined in Embodiment No. 57.

Embodiment No. 103 is directed to compounds of formula IA wherein substituent A is as defined in Embodiment No. 71 and substituent B is as defined in Embodiment No. 58.

Embodiment No. 104 is directed to compounds of formula IA wherein substituent A is as defined in Embodiment No. 71 and substituent B is as defined in Embodiment No. 59.

Embodiment No. 105 is directed to compounds of formula IA wherein substituent A is as defined in Embodiment No. 72 and substituent B is as defined in Embodiment No. 57.

Embodiment No. 106 is directed to compounds of formula IA wherein substituent A is as defined in Embodiment No. 72 and substituent B is as defined in Embodiment No. 58.

Embodiment No. 107 is directed to compounds of formula IA wherein substituent A is as defined in Embodiment No. 72 and substituent B is as defined in Embodiment No. 59.

Embodiment No. 108 is directed to compounds of formula IA wherein substituent A is as defined in Embodiment No. 73 and substituent B is as defined in Embodiment No. 57.

Embodiment No. 109 is directed to compounds of formula IA wherein substituent A is as defined in Embodiment No. 73 and substituent B is as defined in Embodiment No. 58.

Embodiment No. 110 is directed to compounds of formula A wherein substituent A is as defined in Embodiment No. 73 and substituent B is as defined in Embodiment No. 59.

Embodiment No. 111 is directed to any one of the Embodiment Nos. 1 to 110 wherein the compound of formula IA is a pharmaceutically acceptable salt,

Embodiment No. 112 is directed to any one of the Embodiment Nos. 1 to 110 wherein the compound of formula IA is a sodium salt.

Embodiment No. 113 is directed to any one of the Embodiment Nos. 1 to 110 wherein the compound of formula IA is a calcium salt.

Embodiment No. 114 is directed to a pharmaceutically acceptable salt of any one of the representative compounds of this invention that are described below.

Embodiment No. 115 is directed to a sodium salt of any one of the representative compounds described below.

Embodiment No, 116 is directed to a calcium salt of any one of the representative compounds described below.

Embodiment No. 117 is directed to a pharmaceutical composition comprising at least one (e.g., 1 to 3, usually 1) compound of formula IA as described in any one of Embodiment Nos. 1 to 116 in combination with a pharmaceutically acceptable carrier (or diluent). When more than one compound is used each compound is independently selected from the group consisting of Embodiment Nos. 1 to 116.

Embodiment No. 118 is directed to a method of treating any one of the diseases or conditions described herein (i.e., the chemokine mediated diseases or conditions) comprising administering to a patient in need of such treatment an effective amount (e.g., a therapeutically effective amount) of a compound of formula IA as described in any one of the Embodiment Nos. 1 to 116.

Embodiment No. 119 is directed to a method of treating any one of the diseases or conditions described herein (i.e., the chemokine mediated diseases or conditions) comprising administering to a patient in need of such treatment an effective amount (e.g., a therapeutically effective amount) of the pharmaceutical composition described in Embodiment No. 117.

Embodiment No. 120 is directed to a method of treating rheumatoid arthritis in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually one) compound from any of Embodiment Nos. 1 to 116. When more than one compound is used each compound is independently selected from the group consisting of Embodiment Nos. 1 to 116.

Embodiment No. 121 is directed to a method of treating rheumatoid arthritis in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition described in Embodiment No. 117.

Embodiment No. 122 is directed to a method of treating rheumatoid arthritis in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually 1) compound from any of Embodiment Nos. 1 to 116 in combination with at least one compound selected from the group consisting of COX-2 inhibitors, COX inhibitors, immunosuppressives (e.g., methotrexate, cyclosporin, leflunimide and sulfasalazine), steroids (e.g., betamethasone, cortisone and dexamethasone), PDE IV inhibitors, anti-TNF-α compounds, MMP inhibitors, glucocorticoids, chemokine inhibitors, CB2-selective inhibitors, and other classes of compounds indicated for the treatment of rheumatoid arthritis. When more than one compound of Embodiment Nos. 1 to 116 is used, each compound is independently selected from said Embodiment Numbers.

Embodiment No. 123 is directed to a method of treating rheumatoid arthritis in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition described in Embodiment 117 in combination with at least one compound selected from the group consisting of COX-2 inhibitors, COX inhibitors, immunosuppressives (e.g., methotrexate, cyclosporin, leflunimide and sulfasalazine), steroids (e.g., betamethasone, cortisone and dexamethasone), PDE IV inhibitors, anti-TNF-α compounds, MMP inhibitors, glucocorticoids, chemokine inhibitors, CB2-selective inhibitors, and other classes of compounds indicated for the treatment of rheumatoid arthritis.

Embodiment No. 124 is directed to a method of treating COPD in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually one) compound from any of Embodiment Nos. 1 to 116. When more than one compound is used each compound is independently selected from the group consisting of Embodiment Nos. 1 to 116.

Embodiment No. 125 is directed to a method of treating COPD in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition described in Embodiment 117.

Embodiment No. 126 is directed to a method of treating pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually one) compound from any of Embodiment Nos. 1 to 116. When more than one compound is used each compound is independently selected from the group consisting of Embodiment Nos. 1 to 116.

Embodiment No. 127 is directed to a method of treating pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition described in Embodiment 117.

Embodiment No. 128 is directed to a method of treating pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually one) compound from any of Embodiment Nos. 1 to 116, and administering a therapeutically effective amount of at least one medicament selected from the group consisting of NSAIDs, COXIB inhibitors, anti-depressants and anti-convulsants. When more than one compound is used each to compound is independently selected from the group consisting of Embodiment Nos. 1 to 116.

Embodiment No. 129 is directed to a method of treating pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition described in Embodiment 117, and administering a therapeutically effective amount of at least one medicament selected from the group consisting of NSAIDs, COXIB inhibitors, anti-depressants and anti-convulsants.

Embodiment No. 130 is directed to a method of treating pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually one) compound from any of Embodiment Nos. 1 to 116, and administering a therapeutically effective amount of at least one NSAID. When more than one compound is used each compound is independently selected from the group consisting of Embodiment Nos. 1 to 116.

Embodiment No. 131 is directed to a method of treating pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition described in Embodiment 117, and administering a therapeutically effective amount of at least one NSAID.

Embodiment No. 132 is directed to a method of treating pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually one) compound from any of Embodiment Nos. 1 to 116, and administering a therapeutically effective amount of at least one COXIB inhibitor. When more than one compound is used each compound is independently selected from the group consisting of Embodiment Nos. 1 to 116.

Embodiment No. 133 is directed to a method of treating pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition described in Embodiment 117, and administering a therapeutically effective amount of at least one COXIB inhibitor.

Embodiment No. 134 is directed to a method of treating pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually one) compound from any of Embodiment Nos. 1 to 116 and administering a therapeutically effective amount of at least one anti-depressant. When more than one compound is used each compound is to independently selected from the group consisting of Embodiment Nos. 1 to 116.

Embodiment No. 135 is directed to a method of treating pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition described in Embodiment 117 and administering a therapeutically effective amount of at least one anti-depressant.

Embodiment No. 136 is directed to a method of treating pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually one) compound from any of Embodiment Nos. 1 to 116, and administering a therapeutically effective amount of at least one anti-convulsant. When more than one compound is used each compound is independently selected from the group consisting of Embodiment Nos. 1 to 116.

Embodiment No. 137 is directed to a method of treating pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition described in Embodiment 117, and administering a therapeutically effective amount of at least one anti-convusant.

Embodiment No. 138 is directed to a method of treating pain in any one of Embodiment Nos. 128-131 wherein said NSAID is selected from the group consisting of: piroxicam, ketoprofen, naproxen, indomethacin, and ibuprofen.

Embodiment No. 139 is directed to a method of treating pain in any one of Embodiment Nos. 128, 129, 132 and 133 wherein said COXIB inhibitor is selected from the group consisting of: rofecoxib and celecoxib.

Embodiment No. 140 is directed to a method of treating pain in any one of Embodiment Nos. 128, 129, 134 and 135 wherein said anti-depressant is selected from the group consisting of: amitriptyline and nortriptyline.

Embodiment No. 141 is directed to a method of treating pain in any one of Embodiment Nos. 128, 129, 136 and 137 wherein said anti-convulsant is selected from the group consisting of, gabapentin, carbamazepine, pregabalin, and lamotragine.

Embodiment No. 142 is directed to a method of treating pain described by any one of Embodiment Nos. 126 to 141 wherein the pain treated is pain associated with: allodynia, ankylosing spondylitis, appendicitis, autoimmune disorders, bacterial infections, Behcet's syndrome, broken bones, bronchitis, burns, bursitis, cancer including metastatic cancer, candidiasis, cardiovascular conditions, casualgia, chemical injury, childbirth (e.g., labor), chronic regional neuropathies, Crohn's disease, colorectal cancer, connective tissue injuries, conjunctivitis, COPD, decreased intracranial pressure, dental procedures, dermatitis, diabetes, diabetic neuropathy, dysesthesia, dysmenorrhea, eczema, emphysema, fever, fibromyalgia, gastric ulcer, gastritis, giant cell arteritis, gingivitis, gout, gouty arthritis, headache, headache pain resulting from lumbar puncture, headaches including migraine headache, herpes simplex virus infections, HIV, Hodgkin's disease, hyperalgesia, hypersensitivity, inflammatory bowel disease, increased intracranial pressure, irritable bowel syndrome, ischemia, juvenile arthritis, kidney stones, lumbar spondylanhrosis, lower back, upper back and lumbrosacral conditions, lumbar spondylarthrosis, menstrual cramps, migraines, minor injuries, multiple sclerosis, myasthenia gravis, myocarditis, muscle strains, musculoskeletal conditions, myocardial ischemia, nephritic syndrome, nerve root avulsion, neuritis, nutritional deficiency, ocular and corneal conditions, ocular photophobia, ophthalmic diseases, osteoarthritis, otic surgery, otitis externa, otitis media, periarteritis nodosa, peripheral neuropathies, phantom limb pain, polymyositis, post-herpetic neuralgia, post-operative/surgical recovery, post-thoracotomy, psoriatic arthritis, pulmonary fibrosis, pulmonary edema, radiculopathy, reactive arthritis, reflex sympathetic dystrophy, retinitis, retinopathies, rheumatic fever, rheumatoid arthritis, sarcoidosis, sciatica, scleroderma, sickle cell anemia, sinus headaches, sinusitis, spinal cord injury, spondyloarthropathies, sprains, stroke, swimmer's ear, tendonitis, tension headaches, thalamic syndrome, thrombosis, thyroiditis, toxins, traumatic injury, trigeminal neuralgia, ulcerative colitis, urogenital conditions, uveitis, vaginitis, vascular diseases, vasculitis, viral infections and/or wound healing.

Embodiment No. 143 is directed to a method of treating acute pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually one) compound from any of Embodiment Nos. 1 to 116. When more than one compound is used each compound is independently selected from the group consisting of Embodiment Nos. 1 to 116.

Embodiment No. 144 is directed to a method of treating acute pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition described in Embodiment No. 117.

Embodiment No. 145 is directed to a method of treating acute inflammatory pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually one) compound from any of Embodiment Nos. 1 to 116. When more than one compound is used each compound is independently selected from the group consisting of Embodiment Nos. 1 to 116.

Embodiment No. 146 is directed to a method of treating acute inflammatory pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition described in Embodiment No. 117.

Embodiment No. 147 is directed to a method of treating chronic inflammatory pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually one) compound from any of Embodiment Nos. 1 to 116. When more than one compound is used each compound is independently selected from the group consisting of Embodiment Nos. 1 to 116.

Embodiment No. 148 is directed to a method of treating chronic inflammatory pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition described in Embodiment No. 117.

Embodiment No. 149 is directed to a method of treating neuropathic pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually one) compound from any of Embodiment Nos. 1 to 116. When more than one compound is used each compound is independently selected from the group consisting of Embodiment Nos. 1 to 116.

Embodiment No. 150 is directed to a method of treating neuropathic pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition described in Embodiment No. 117.

Embodiment No. 151 is directed to a method of treating pain as described in any of Embodiment Nos. 128 to 141 wherein said pain is acute pain.

Embodiment No. 152 is directed to a method of treating pain as described in any of Embodiment Nos. 128 to 141 wherein said pain is acute inflammatory pain.

Embodiment No. 153 is directed to a method of treating pain as described in any of Embodiment Nos. 128 to 141 wherein said pain is chronic inflammatory pain.

Embodiment No. 154 is directed to a method of treating pain as described in any of Embodiment Nos. 128 to 141 wherein said pain is neuropathic pain.

Embodiment No. 155 is directed to a method of treating arthritis in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually one) compound from any of Embodiment Nos. 1 to 116. When more than one compound is used each compound is independently selected from the group consisting of Embodiment Nos. 1 to 116.

Embodiment No. 156 is directed to a method of treating arthritis in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition described in Embodiment No. 117.

Embodiment No. 157 is directed to a method of treating osteoarthritis in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually one) compound from any of Embodiment Nos. 1 to 116. When more than one compound is used each compound is independently selected from the group consisting of Embodiment Nos. 1 to 116.

Embodiment No. 158 is directed to a method of treating osteoarthritis in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition described in Embodiment No. 117.

Representative compounds include the final compounds of Examples 1, 2-4, 6-35, 100-105, 107, 108, 110, 111, 112, 114-116, 118-132, 134-145, 148, 180, 182, 183, 185, 186, 188, 300-389, 500-639, 700-787, and 900-987, or the pharmaceutically acceptable salts thereof.

Preferred compounds of the invention are the final compounds of Examples 1, 6, 8, 110, 111, 112, 114, 122, 120, 123, 124, 127, 128, 129, 130, 131, 139, 142, 144, 145, 300, 305, 306, 307, 313, 316, 317, 318, 323, 324, 327, 328, 329, 330, 334, 335, 338, 339, 340, 349, 350, 351, 359, 360, 361, 362, 364, 370, 372, 373, 374, 381, 544, 545, 546, 548, 558, 559, 560, 561, 562, 572, 573, 587, 601, 616, 708, 718, 719, 721, 732, 754, 774, 784, 928, 930, 931, 939, 942, 941, 950, 952, or the pharmaceutically acceptable salts thereof.

More preferred compounds of the invention are the final compounds of Examples 1, 6, 8, 110, 111, 112, 114, 122, 120, 123, 124, 129, 130, 131, 142, 144, 145, 300, 305, 306, 307, 313, 316, 317, 318, 323, 324, 327, 328, 329, 334, 335, 338, 339, 340, 349, 350, 351, 359, 360, 361, 362, 364, 370, 372, 373, 374, 381, 544, 545, 546, 548, 558, 559, 560, 561, 562, 572, 708, 718, 719, 721, 732, 754, 774, 784, 928, 930, 931, 939, 942, 941, 950, 952, or the pharmaceutically acceptable salts thereof.

Most preferred compounds of the invention are the final compounds of Examples 1, 6, 8, 114, 120, 123, 129, 131, 300, 305, 306, 307, 316, 317, 318, 323, 327, 328, 329, 334, 359, 360, 361, 370, 372, 373, 374, 544, 545, 546, 548, 558, 559, 560, 561, 562, 928, 930, 931, 939, 942, 941, 950, 952, or the pharmaceutically acceptable salts thereof.

Certain compounds of the invention may exist in different stereoisomeric forms (e.g., enantiomers, diastereoisomers and atropisomers). The invention contemplates all such stereoisomers both in pure form and in admixture, including racemic mixtures. Isomers can be prepared using conventional methods.

All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates and prodrugs of the compounds as well as the salts and solvates of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms “salt”, “solvate” “prodrug” and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugs of the inventive compounds.

Certain compounds will be acidic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.

Certain basic compounds also form pharmaceutically acceptable salts, e.g., acid addition salts. For example, the pyrido-nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the invention.

All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.

Compounds of formula IA can exist in unsolvated and solvated forms (or compounds of formula IA can optionally be converted to a solvate), including hydrated forms. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like, are equivalent to the unsolvated forms for the purposes of this invention.

Preparation of Solvates is Generally Known. Thus, for Example, M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001). A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example I.R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).

This invention also includes Prodrugs of the novel compounds of this invention. The term “prodrug,” as used herein, represents compounds that are rapidly transformed in vivo to the parent compound (i.e., a compound of formula IA), for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

This invention also includes the compounds of this invention in isolated and pure form.

This invention also includes polymorphic forms of the compounds of this invention. The polymorphic forms of the compounds of formula IA, and of the salts, solvates and prodrugs of the compounds of formula IA, are intended to be included in the present invention.

For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington: The Science and Practice of Pharmacy, 20^(th) Edition, (2000), Lippincott Williams & Wilkins, Baltimore, Md.

Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.

Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally. The transdermal composition can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.01 mg to about 1000 mg, preferably from about 0.01 mg to about 750 mg, more preferably from about 0.01 mg to about 500 mg, and most preferably from about 0.01 mg to about 250 mg, according to the particular application.

The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total dosage may be divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 0.04 mg/day to about 4000 mg/day, in two to four divided doses.

Classes of compounds that can be used as the chemotherapeutic agent (antineoplastic agent) include: alkylating agents, antimetabolites, natural products and their derivatives, hormones and steroids (including synthetic analogs), and synthetics. Examples of compounds within these classes are given below.

Alkylating agents (including nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes): Uracil mustard, Chlormethine, Cyclophosphamide (Cytoxan®), Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylene-melamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, and Temozolomide.

Antimetabolites (including folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors): Methotrexate, 5-Fluorouracil, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, Pentostatine, and Gemcitabine.

Natural products and their derivatives (including vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins): Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, paclitaxel (paclitaxel is commercially available as Taxol® and is described in more detail below in the subsection entitled “Microtubule Affecting Agents”), Mithramycin, Deoxyco-formycin, Mitomycin-C, L-Asparaginase, Interferons (especially IFN-a), Etoposide, and Teniposide.

Hormones and steroids (including synthetic analogs): 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Tamoxifen, Methylprednisolone, Methyl-testosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, Zoladex.

Synthetics (including inorganic complexes such as platinum coordination complexes): Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, and Hexamethylmelamine.

Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in the standard literature. For example, the administration of many of the chemotherapeutic agents is described in the “Physicians' Desk Reference” (PDR), e.g., Physician's Desk Reference, 57^(th) edition, 2003, Thompson PDR at Montvale, N.J. 07645-1742, USA; the disclosure of which is incorporated herein by reference thereto.

As used herein, a microtubule affecting agent is a compound that interferes with cellular mitosis, i.e., having an anti-mitotic effect, by affecting microtubule formation and/or action. Such agents can be, for instance, microtubule stabilizing agents or agents that disrupt microtubule formation.

Microtubule affecting agents useful in the invention are well known to those of skill in the art and include, but are not limited to allocolchicine (NSC 406042), Halichondrin B (NSC 609395), colchicine (NSC 757), colchicine derivatives (e.g., NSC 33410), dolastatin 10 (NSC 376128), maytansine (NSC 153858), rhizoxin (NSC 332598), paclitaxel (Taxol®, NSC 125973), Taxol® derivatives (e.g., derivatives (e.g., NSC 608832), thiocolchicine (NSC 361792), trityl cysteine (NSC 83265), vinblastine sulfate (NSC 49842), vincristine sulfate (NSC 67574), epothilone A, epothilone, and discodermolide (see Service, (1996) Science, 274:2009) estramustine, nocodazole, MAP4, and the like. Examples of such agents are also described in the scientific and patent literature, see, e.g., Bulinski (1997) J. Cell Sci. 110:3055-3064; Panda (1997) Proc. Natl. Acad. Sci. USA 94:10560-10564; Muhiradt (1997) Cancer Res. 57:3344-33467 Nicolaou (1997) Nature 387:268-272; Vasquez (1997) Mol. Biol. Cell 8:973-985; Panda (1996) J. Biol. Chem. 271:29807-29812.

Particularly preferred agents are compounds with paclitaxel-like activity. These include, but are not limited to paclitaxel and paclitaxel derivatives (paclitaxel-like compounds) and analogues. Paclitaxel and its derivatives are available commercially. In addition, methods of making paclitaxel and paclitaxel derivatives and analogues are well known to those of skill in the art (seer e.g., U.S. Pat. Nos. 5,569,729; 5,565,478; 5,530,020; 5,527,924; 5,508,447; 5,489,589; 5,488,116; 5,484,809; 5,478,854; 5,478,736; 5,475,120; 5,468,769, 5,461,169; 5,440,057; 5,422,364; 5,411,984; 5,405,972; and 5,296,506).

More specifically, the term “paclitaxel” as used herein refers to the drug commercially available as Taxol® (NSC number: 125973). Taxol® inhibits eukaryotic cell replication by enhancing polymerization of tubulin moieties into stabilized microtubule bundles that are unable to reorganize into the proper structures for mitosis. Of the many available chemotherapeutic drugs, paclitaxel has generated interest because of its efficacy in clinical trials against drug-refractory tumors, including ovarian and mammary gland tumors (Hawkins (1992) Oncology, 6: 17-23, Horwitz (1992) Trends Pharmacol. Sci. 13: 134-146, Rowinsky (1990) J. Natl. Canc. Inst. 82: 1247-1259).

Additional microtubule affecting agents can be assessed using one of many such assays known in the art, e.g., a semiautomated assay which measures the tubulin-polymerizing activity of paclitaxel analogs in combination with a cellular assay to measure the potential of these compounds to block cells in mitosis (see Lopes (1997) Cancer Chemother. Pharmacol. 41:37-47).

Generally, activity of a test compound is determined by contacting a cell with that compound and determining whether or not the cell cycle is disrupted, in particular, through the inhibition of a mitotic event. Such inhibition may be mediated by disruption of the mitotic apparatus, e.g., disruption of normal spindle formation. Cells in which mitosis is interrupted may be characterized by altered morphology (e.g., microtubule compaction, increased chromosome number, etc.).

Compounds with possible tubulin polymerization activity can be screened in vitro. In a preferred embodiment, the compounds are screened against cultured WR21 cells (derived from line 69-2 wap-ras mice) for inhibition of proliferation and/or for altered cellular morphology, in particular for microtubule compaction. In vivo screening of positive-testing compounds can then be performed using nude mice bearing the WR21 tumor cells, Detailed protocols for this screening method are described by Porter (1995) Lab. Anim. Sci., 45(2):145-150.

Other methods of screening compounds for desired activity are well known to those of skill in the art. Typically such assays involve assays for inhibition of microtubule assembly and/or disassembly. Assays for microtubule assembly are described, for example, by Gaskin et al. (1974) J. Molec. Biol., 89: 737-758. U.S. Pat. No. 5,569,720 also provides in vitro and in vivo assays for compounds with paclitaxel-like activity.

Methods for the safe and effective administration of the above-mentioned microtubule affecting agents are known to those skilled in the art. In addition, their administration is described in the standard literature. For example, the administration of many of the chemotherapeutic agents is described in the “Physicians' Desk Reference” (PDR), e.g., 1996 edition (Medical Economics Company, Montvale, N.J. 07645-1742, USA); the disclosure of which is incorporated herein by reference thereto.

The amount and frequency of administration of the compounds of formula IA and the chemotherapeutic agents and/or radiation therapy will be regulated according to the judgment of the attending clinician (physician) considering such factors as age, condition and size of the patient as well as severity of the disease being treated. A dosage regimen of the compound of formula IA can be oral administration of from 10 mg to 2000 mg/day, preferably 10 to 1000 mg/day, more preferably 50 to 600 mg/day, in two to four (preferably two) divided doses, to block tumor growth. Intermittant therapy (e.g., one week out of three weeks or three out of four weeks) may also be used.

The chemotherapeutic agent and/or radiation therapy can be administered according to therapeutic protocols well known in the art. It will be apparent to those skilled in the art that the administration of the chemotherapeutic agent and/or radiation therapy can be varied depending on the disease being treated and the known effects of the chemotherapeutic agent and/or radiation therapy on that disease. Also, in accordance with the knowledge of the skilled clinician, the therapeutic protocols (e.g., dosage amounts and times of administration) can be varied in view of the observed effects of the administered therapeutic agents (e.g., antineoplastic agent or radiation) on the patient, and in view of the observed responses of the disease to the administered therapeutic agents.

In the methods of this invention, a compound of formula IA is administered concurrently or sequentially with a chemotherapeutic agent and/or radiation. Thus, it is not necessary that, for example, the chemotherapeutic agent and the compound of formula IA, or the radiation and the compound of formula IA, should be administered simultaneously or essentially simultaneously. The advantage of a simultaneous or essentially simultaneous administration is well within the determination of the skilled clinician.

Also, in general, the compound of formula IA and the chemotherapeutic agent do not have to be administered in the same pharmaceutical composition, and may, because of different physical and chemical characteristics, have to be administered by different routes. For example, the compound of formula IA may be administered orally to generate and maintain good blood levels thereof, while the chemotherapeutic agent may be administered intravenously. The determination of the mode of administration and the advisability of administration, where possible, in the same pharmaceutical composition, is well within the knowledge of the skilled clinician. The initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and is times of administration can be modified by the skilled clinician.

The particular choice of a compound of formula IA, and chemo-therapeutic agent and/or radiation will depend upon the diagnosis of the attending physicians and their judgement of the condition of the patient and the appropriate treatment protocol.

The compound of formula IA, and chemotherapeutic agent and/or radiation may be administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending upon the nature of the proliferative disease, the condition of the patient, and the actual choice of chemotherapeutic agent and/or radiation to be administered in conjunction (i.e., within a single treatment protocol) with the compound of formula or IA.

If the compound of formula IA, and the chemotherapeutic agent and/or radiation are not administered simultaneously or essentially simultaneously, then the initial order of administration of the compound of formula IA, and the chemotherapeutic agent and/or radiation, may not be important. Thus, the compound of formula IA may be administered first, followed by the administration of the chemotherapeutic agent and/or radiation; or the chemo-therapeutic agent and/or radiation may be administered first, followed by the administration of the compound of formula IA. This alternate administration may be repeated during a single treatment protocol. The determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the disease being treated and the condition of the patient.

For example, the chemotherapeutic agent and/or radiation may be administered first, especially if it is a cytotoxic agent, and then the treatment continued with the administration of the compound of formula IA followed, where determined advantageous, by the administration of the chemotherapeutic agent and/or radiation, and so on until the treatment protocol is complete.

Thus, in accordance with experience and knowledge, the practicing physician can modify each protocol for the administration of a component (therapeutic agent—i.e., the compound of formula IA, chemotherapeutic agent or radiation) of the treatment according to the individual patient's needs, as the treatment proceeds.

The attending clinician, in judging whether treatment is effective at the dosage administered, will consider the general well-being of the patient as well as more definite signs such as relief of disease-related symptoms, inhibition of tumor growth, actual shrinkage of the tumor, or inhibition of metastasis. Size of the tumor can be measured by standard methods such as radio-logical studies, e.g., CAT or MRI scan, and successive measurements can be used to judge whether or not growth of the tumor has been retarded or even reversed. Relief of disease-related symptoms such as pain, and improvement in overall condition can also be used to help judge effectiveness of treatment.

BIOLOGICAL EXAMPLES

The compounds of the present invention are useful in the treatment of CXC-chemokine mediated conditions and diseases. This utility is manifested in their ability to inhibit IL-8 and GRO-α chemokine as demonstrated by the following in vitro assays.

Receptor Binding Assays:

CXCR1 SPA Assay

For each well of a 96 well plate, a reaction mixture of 10 μg hCXCR1-CHO overexpressing membranes (Biosignal) and 200 μg/well WGA-SPA beads (Amersham) in 100 μl was prepared in CXCR1 assay buffer (25 mM HEPES, pH 7.8, 2 mM CaCl₂, 1 mM MgCl₂, 125 mM NaCl, 0.1% BSA) (Sigma). A 0.4 nM stock of ligand, [125I]-IL-8 (NEN) was prepared in the CXCR1 assay buffer 20× stock solutions of test compounds were prepared in DMSO (Sigma). A 6× stock solution of IL-8 (R&D) was prepared in CXCR2 assay buffer. The above solutions were added to a 96-well assay plate (PerkinElmer) as follows: 10 μl test compound or DMSO, 40 μl CXCR1 assay buffer or IL-8 stock, 100 μl of reaction mixture, 50 μl of ligand stock (Final [Ligand]=0.1 nM). The assay plates were shaken for 5 minutes on plate shaker, then incubated for 8 hours before cpm/well were determined in Microbeta Trilux counter (PerkinElmer). % Inhibition of Total binding-NSB (250 nM IL-8) was determined for IC₅₀ values.

Alternative CXCR1 SPA Assay

Protocol Using CXCR1-Expressing Membranes from Biosignal Packard

For each 50 μl reaction, a working stock of 0.25 μg/μl hCXCR1-CHO over-expressing membranes with a specific activity of 0.05 pmol/mg (Biosignal Packard) and 25 μg/μl WGA-SPA beads (Perkin Elmer Life Sciences) was prepared in CXCR1 assay buffer (25 mM HEPES, pH 7.8, 0.1 mM CaCl₂, 1 mM MgCl₂, 100 mM NaCl) (Sigma). This mixture was incubated on ice for 30 minutes and then centrifuged at 2500 rpm for 5 minutes. The beads and membranes were resuspended in CXCR1 assay buffer to the same concentrations as in the original mixture. A 0.125 nM stock of ligand, [¹²⁵I]-IL-8 (Perkin Elmer Life Sciences), was prepared in the CXCR1 assay buffer. Test compounds were first serially diluted by half-logs in DMSO (Sigma) and then diluted 20-fold in CXCR1 assay buffer. The above solutions were added to a Corning NBS (non-binding surface) 96-well assay plate as follows: 20 μl test compound or 5% DMSO (final [DMSO]=2%), 20 μl of membranes and SPA bead mixture (Final [membrane]=5 μg/reaction; Final [SPA bead]=500 μg/reaction), 10 μl of ligand stock (Final [¹²⁵I-IL-8]=0.025 nM). The assay plates were incubated for 4 hours before cpm/well were determined in a Microbeta Trilux counter (Perkin Elmer Life Sciences). IC₅₀ values were quantified using nonlinear regression analysis in GraphPad Prism.

Alternative CXCR1 SPA Assay

Protocol Using CXCR1-Expressing Membranes from Euroscreen

For each 50 μl reaction, a working stock of 0.025 μg/μl hCXCR1-CHO over-expressing membranes with a specific activity of 3.47 pmol/mg (Euroscreen) and 5 μg/μl WGA-SPA beads (Perkin Elmer Life Sciences) was prepared in CXCR1 assay buffer (25 mM HEPES, pH 7.8, 2.0 mM CaCl₂, 1 mM MgCl₂, 125 mM NaCl) (Sigma). This mixture was incubated on ice for 5 minutes, A 0.125 nM stock of ligand, [¹²⁵I]-IL-8 (Perkin Elmer Life Sciences), was prepared in the CXCR1 assay buffer. Test compounds were first serially diluted by half-logs in DMSO (Sigma) and then diluted 13.3-fold in CXCR1 assay buffer. The above solutions were added to a Corning NBS (non-binding surface) 96-well assay plate as follows: 20 μl test compound or 7.5% DMSO (final [DMSO]=3%), 20 μl of membranes and SPA bead mixture (Final [membrane]=0.5 μg/reaction; Final [SPA bead]=100 μg reaction), 10 μl of ligand stock (Final [¹²⁵I-IL-8]=0.025 nM). The assay plates were incubated for 4 hours before cpm/well were determined in a Microbeta Trilux counter (Perkin Elmer Life Sciences). IC₅₀ values were quantified using nonlinear regression analysis in GraphPad Prism.

For the CXCR1 assay, the compounds of Examples 1 to 35 had a K_(i) within the range of 91 nM to 23,000 nM. The compound of Example 6 had a K_(i) of 91 nM, and the compound of Example 1 had a K_(i) of 808 nM.

CXCR2 SPA Assay

For each well of a 96 well plate, a reaction mixture of 4 μg hCXCR2-CHO overexpressing membranes (Biosignal) and 200 μg/well WGA-SPA beads (Amersham) in 100 μl was prepared in CXCR2 assay buffer (25 mM HEPES, pH 7.4, 2 mM CaCl₂, 1 mM MgCl₂). A 0.4 nM stock of ligand, [125I]-IL-8 (NEN), was prepared in the CXCR2 assay buffer, 20× stock solutions of test compounds were prepared in DMSO (Sigma). A 6× stock solution of GRO-α (R&D) was prepared in CXCR2 assay buffer. The above solutions were added to a 96-well assay plate (PerkinElmer or Corning) as follows: 10 μl test compound or DMSO, 40 ul CXCR2 assay buffer or GRO-α stock, 100 μl of reaction mixture, 50 μl of ligand stock (Final [Ligand]=0.1 nM). When 40× stock solutions of test compounds in DMSO were prepared, then the above protocol was used except instead 5 μl test compound or DMSO and 45 μl CXCR2 assay buffer were used. The assay plates were shaken for 5 minutes on a plate shaker, then incubated for 2-8 hours before cpm/well were determined in Microbeta Trilux counter (PerkinElmer). % Inhibition of total binding minus non-specific binding (250 nM Gro-α or 50 μM antagonist) was determined and IC50 values calculated. Compounds of this invention had an IC₅₀ of <5 μM.

Alternative CXCR2 SPA Assay

Protocol Using the CXCR2 50 μl Assay

For each 50 μl reaction, a working stock of 0.031 μg/μl hCXCR2-CHO over-expressing membranes with a specific activity of 0.4 pmol/mg (Biosignal Packard) and 2.5 μg/μl WGA-SPA beads (Perkin Elmer Life Sciences) was prepared in CXCR2 assay buffer (25 mM HEPES, pH 7.4, 2.0 mM CaCl₂, 1 mM MgCl₂) (Sigma). This mixture was incubated on ice for 5 minutes. A 0.50 nM stock of ligand, [¹²⁵I]-IL-8 (Perkin Elmer Life Sciences), was prepared in the CXCR2 assay buffer. Test compounds were first serially diluted by half-logs in DMSO (Sigma) and then diluted 13.3-fold in CXCR2 assay buffer. The above solutions were added to a Corning NBS (non-binding surface) 96-well assay plate as follows: 20 μl test compound or 7.5% DMSO (final [DMSO]=3%), 20 μl of membranes and SPA bead mixture (final [membrane]=0.625 μg/reaction; final [SPA bead]=50 μg/reaction), 10 μl of ligand stock (final [¹²⁵I-IL-8]=0.10 nM). The assay plates were incubated for 2 hours before cpm/well were determined in a Microbeta Trilux counter (Perkin Elmer Life Sciences). IC₅₀ values were quantified using nonlinear regression analysis in GraphPad Prism.

Alternative CXCR2 SPA Assay

Protocol Using the CXCR2 200 μl Assay

For each 200 μl reaction, a working stock of 0.02 μg/μl hCXCR2-CHO over-expressing membranes with a specific activity of 0.6 pmol/mg (Biosignal Packard) and 2 μg/μl WGA-SPA beads (Perkin Elmer Life Sciences) was prepared in CXCR2 assay buffer (25 mM HEPES, pH 7.4, 2.0 mM CaCl₂, 1 mM MgCl₂) (Sigma). This mixture was incubated on ice for 5 minutes. A 0.40 nM stock of ligand, [¹²⁵I]-IL-8 (Perkin Elmer Life Sciences), was prepared in the CXCR2 assay buffer. Test compounds were first serially diluted by half-logs in DMSO (Sigma) and then diluted 20-fold in CXCR2 assay buffer. The above solutions were added to a Corning NBS (non-binding surface) 96-well assay plate as follows: 50 μl test compound or 10% DMSO (final [DMSO]=2.5%), 100 μl of membranes and SPA bead mixture (final [membrane]=2 μg/reaction; final [SPA bead]=200 μg/reaction), 50 μl of ligand stock (final [¹²⁵I-IL-8]=0.10 nM). The assay plates were incubated for 2 hours before cpm/well were determined in a Microbeta Trilux counter (Perkin Elmer Life Sciences). IC₅₀ values were quantified using nonlinear regression analysis in GraphPad Prism.

For the CXCR2 assay, the compounds of Examples 1 to 35 had a K_(i) within the range of 7.5 nM to 1,900 nM. The compound of Example 6 had a K_(i) of 14 nM, and the compound of Example 1 had a K_(i) of 28 nM.

Calcium Fluorescence Assay (FLIPR)

HEK 293 cells stably transfected with hCXCR2 and Gαι/q were plated at 10,000 cells per well in a Poly-D-Lysine Black/Clear plate (Becton Dickinson) and incubated 48 hours at 5% CO₂, 37° C. The cultures were then incubated with 4 mM fluo-4, AM (Molecular Probes) in Dye Loading Buffer (1% FBS, HBSS w. Ca & Mg, 20 mM HEPES (Cellgro), 2.5 mM Probenicid (Sigma) for 1 hour. The cultures were washed with wash buffer (HBSS w Ca, & Mg, 20 mM HEPES, Probenicid (2.5 mM)) three times, then 100 μl/well wash buffer was added.

During incubation, compounds were prepared as 4× stocks in 0.4% DMSO (Sigma) and wash buffer and added to their respective wells in the first addition plate. IL-8 or GRO-α (R&D Systems) concentrations were prepared 4× in wash buffer+0.1% BSA and added to their respective wells in second addition plate.

Culture plate and both addition plates were then placed in the FLIPR imaging system to determine change in calcium fluorescence upon addition of compound and then ligand. Briefly, 50 μl of compound solutions or DMSO solution was added to respective wells and change in calcium fluorescence measured by the FLIPR for 1 minute. After a 3 minute incubation within the instrument, 50 μl of ligand was then added and the change in calcium fluorescence measured by the FLIPR instrument for 1 minute. The area under each stimulation curve was determined and values used to determine % Stimulation by compound (agonist) and % Inhibition of Total Calcium response to ligand (0.3 nM IL-8 or GRO-α) for IC50 values of the test compounds,

Chemotaxis Assays for 293-CXCR2

A chemotaxis assay is setup using Fluorblok inserts (Falcon) for 293-CXCR2 cells (HEK-293 cells overexpressing human CXCR2). The standard protocol used at present is as follows:

-   1. Inserts are coated with collagen IV (2 ug/ml) for 2 hrs at 37° C. -   2. The collagen is removed and inserts are allowed to air dry     overnight. -   3. Cells are labeled with 10 uM calcein AM (Molecular Probes) for 2     hrs. Labeling is done in complete media with 2% FBS. -   4. Dilutions of compound are made in minimal media (0.1% BSA) and     placed inside the insert which is positioned inside the well of a 24     well plate. Within the well is IL-8 at a concentration of 0.25 nM in     minimal media. Cells are washed and resuspended in minimal media and     placed inside the insert at a concentration of 50,000 cells per     insert. -   5. Plate is incubated for 2 hrs and inserts are removed and placed     in a new 24 well. Fluorescence is detected at excitation=485 nM and     emission=530 nM.     Cytotoxicity Assays

A cytotoxicity assay for CXCR2 compounds is conducted on 293-CXCR2 cells. Concentrations of compounds are tested for toxicity at high concentrations to determine if they may be used for further evaluation in binding and cell based assays. The protocol is as follows:

-   1. 293-CXCR2 cells are plated overnight at a concentration of 5000     cells per well in complete media. -   2. Dilutions of compound are made in minimal media w/0.1% BSA.     Complete media is poured off and the dilutions of compound are     added. Plates are incubated for 4, 24 and 48 hrs. Cells are labeled     with 10 uM calcein AM for 15 minutes to determine cell viability.     Detection method is the same as above.     Soft Agar Assay

10,000 SKMEL-5 cells/well are placed in a mixture of 1.2% agar and complete media with various dilutions of compound. Final concentration of agar is 0.6%. After 21 days viable cell colonies are stained with a solution of MTT (1 mg/ml in PBS). Plates are then scanned to determine colony number and size. IC₅₀ is determined by comparing total area vs. compound concentration.

CCR7 Membrane Preparation.

Ba/F3-CCR7 membranes were prepared as previously described (Hipkin et al., J. Biol. Chem., 272, 1997, 13869-76). Cells were pelleted by centrifugation, incubated in homogenization buffer (10 mM Tris-HCl, 5 mM EDTA, 3 mM EGTA, pH 7.6) and 1 μM PMSF for 30 min. on ice. The cells were then lysed with a Dounce homogenizer using stirrer type RZR3 polytron homogenizer (Caframo, Wiarton, Ont.) with 12 strokes at 900 RPM. The intact cells and nuclei were removed by centrifugation at 500×g for 5 min. The cell membranes in the supernatant were then pelleted by centrifugation at 100,000×g for 30 min. The membranes were then resuspended in glygly buffer (20 mM glycylglycine, 1 mM MgCl₂, 250 mM sucrose, pH 7.2), aliquoted, quick frozen and stored at −80° C.

CCR7 [³⁵S]GTPγS Exchange Assay.

The exchange of guanosine 5′-[γ-³⁵S]triphospate ([³⁵S]GTPγS, triethylammonium salt; specific activity=1250 Ci/mmol; NEN Boston, Mass.) was measured using a scintillation proximity assay (SPA) as previously described (Cox, et. al., Mol. Pharmacol., 59, 2001, 707-15). For each assay point, 2 μg of membrane was preincubated for 30 min at room temperature with 200 μg wheat germ agglutinin-coated SPA beads (WGA-SPA; Amersham, Arlington Heights, Ill.) in SPA binding buffer (50 mM HEPES, 10 mM MgCl₂, 1 mM EDTA, 100 mM NaCl, 0.1% BSA, pH 7.6). The beads and membranes were transferred to a 96-well Isoplate (Wallac, Gaithersburg, Md.) and incubated with 10 μM guanosine 5′-diphosphate (GDP) in the presence or absence of 2 nM MIP-3β and/or compounds for 60 min at room temperature. The incubation continued for another 60 min. following the addition of 0.1 nM [³⁵S]GTPγS. Membrane-bound [³⁵S]GTPγS was measured using a 1450 Microbeta Trilux counter (Wallac, Gaithersburg, Md.).

The compounds of Examples 1 to 35 had an EC₅₀ within the range of 22 nM to 120 μM. The compound of Example 6 had an EC₅₀ of 22 nM, and the compound of Example 3 had an EC₅₀ of 880 nM.

Rat Carrageenan-Induced Thermal Hyperalgesia

Male Sprague-Dawley rats (Charles River Laboratories; 150-200 gm) can be maintained under normal housing and lighting conditions, with food and water supplied ad libitum. Each animal can be tested for its baseline paw withdrawal response to a heat source by placement of the animal into a plantar testing unit (Ugo Basile, Italy), in which a light source is moved under its paw and the time of withdrawal is measured. The animals can then be dosed orally with a compound of this invention, and then can be injected intraplantarly with 2-3 mg lambda carrageenan (FMC Colloids) in 100 ul of saline while under isofurane anesthesia. Three hours later, the animals can be re-measured for their withdrawal response to the heat source. Plantar tissue can also be analyzed for myeloperoxidase levels as a surrogate for neutrophil infiltration.

Compounds of formula IA may be produced by processes known to those skilled in the art, in the following reaction schemes, and in the preparations and examples below.

A general procedure for the preparation of compounds of formula IA is as follows:

Compounds of this invention are prepared by condensing an amine (either A-NH₂ or B-NH₂) with the known diethoxy thiadiazole mono-oxide prepared according to the literature to give the monoethoxy thiadizoleoxide intermediate. Subsequent condensation of this intermediate with the commercially available or prepared amine (either A-NH₂ or B-NH₂) provides the desired 3,4-diamino mono oxide intermediate, which is reduced with triphenylphosphine and carbon tetrachloride in dichloromethane to produce the final thiadiazole chemokine antagonist.

The invention disclosed herein is exemplified by the following preparations and examples which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures may be apparent to those skilled in the art.

Preparative Example 1

3-Nitrosalicylic acid (500 mg, 2.7 mmol), DCC (563 mg) and ethyl acetate (10 mL) were combined and stirred for 10 min. (R)-(−)-2-pyrrolidinemethanol (0.27 mL) was added and the resulting suspension was stirred at room temperature overnight. The solid was filtered and the filtrate washed with 1N NaOH. The aqueous phase was acidified and extracted with EtOAc. The resulting organic phase was dried over anhydrous MgSO₄, filtered and concentrated in vacuo. Purification of the residue by preparative plate chromatography (silica gel, 5% MeOH/CH₂Cl₂ saturated with AcOH) gave the product (338 mg, 46%, MH⁺=267).

Preparative Example 2

Step A

3-Nitrosalicylic acid (9.2 g), bromotripyrrolidinophosphonium hexafluorophosphate (PyBrP, 23 g) and N,N-diisopropylethylamine (DIEA, 26 mL) in anhydrous CH₂Cl₂ (125 mL) were combined and stirred at 25° C. for 30 min. (R)-(+)-3-pyrrolidinol (8.7 g) in CH₂Cl₂ (25 mL) was added over 25 min and the resulting suspension was stirred at room temperature overnight. The mixture was extracted with 1M NaOH (aq) and the organic phase was discarded. The aqueous phase was acidified with 1M HCl (aq), extracted with EtOAc, dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to afford the crude product (7 g) which was used without further purification

Step B

The crude product from Step A above was stirred with 10% Pd/C (0.7 g) in MeOH (100 mL) under a hydrogen gas atmosphere overnight. The reaction mixture was filtered through celite, the filtrate concentrated in vacuo, and the resulting residue purified by column chromatography (silica gel, 10% MeOH/CH₂Cl₂ saturated with NH₄OH) to give the product (2.5 g, 41%, MH+=223).

Preparative Example 2.1

To N-BOC-3-(amino)piperidine (0.5 g) dissolved in CH₂Cl₂ (10 mL) was added benzylisocyanate (3 mmol). After stirring for 2 hrs, amine scavenger resin (1.9 mmol) was added and the mixture was stirred overnight, filtered, the resin back-washed with CH₂Cl₂ and methanol, and the organics concentrated in vacuo. Stirring of the crude material in 4N HCl/dioxane (40 mL) for 2.5 hrs before concentrating in vacuo gave the title compound (41%, MH+=369).

Preparative Example 2.2-2.6

Following the procedures set forth in Preparative Example 2.1 but using the isocyanate (or chloroformate) indicated in the Table below, the amines were obtained and used without further purification.

Prep Ex. Amine Isocyanate Amine 2.2

2.3

2.4

2.5

2.6

Preparative Example 2.7

To N-BOC-3-(amino)piperidine (5 mmol) dissolved in CH₂Cl₂ (30 mL) was added trifluoromethanesulfonic anhydride (5 mmol) and the mixture was stirred overnight. The mixture was concentrated in vacuo, diluted with CH₂Cl₂ (10 mL) and treated with trifluoroacetic acid (10 mL). After stirring for 2 hr, the mixture was concentrated in vacuo to give the title compound (43%, MH+=233.1).

Preparative Example 2.8

Step A

3-Nitrosalicylic acid (5 mmol) and N-hydroxysuccinimide (5 mmol) were added to a solution of 2% DMF/CH₂Cl₂, followed by DCC (5 mmol). After stirring for 2 hr, the mixture was filtered and concentrated in vacuo and the residue used directly in Step B.

Step B

The product from Step A above was suspended in DMF and to this was added morpholino-2-carboxylic acid HCl (5 mmol) in CH₂Cl₂ (10 mL)/DMF (5 mL) and diisopropylethylamine (10 mmol). The mixture was stirred overnight, filtered, basified with 1N NaOH (50 mL), washed with CH₂Cl₂, acidified with 5N HCl and extracted with EtOAc. The organic phase was dried over Na₂SO₄, filtered and concentrated in vacuo to give the desired compound which was used directly in Step C (MH+=296).

Step C

Following a similar procedure as in Preparative Example 2 Step B, but using the product from Step B above, the title compound was obtained (23%, MH+=267).

Preparative Example 2.9

Step A

2-Piperazinecarboxylic acid and 2-chloro-1,3-pyrimidine were stirred with triethylamine and MeOH. After stirring overnight at reflux, the mixture was filtered and concentrated in vacuo to give the desired compound which was used directly in Step B (MH+=209).

Step B

Following a similar procedure as Preparative Example 2.8, Step B except using the product from Preparative Example 2.9 Step A above, the desired compound was obtained (41%, MH+=374).

Step C

Following a similar procedure as in Preparative Example 2, Step B, but using the product from Step B above, the desired compound was obtained (99%, MH+=344).

Preparative Example 2.10

Step A

Following a similar procedure as Preparative Example 2.8, Step A except using 3-nitrobenzoic acid, the desired compound was obtained and used directly in Step B.

Step B

Following a similar procedure as Preparative Example 2.8, Step B except using the products from Preparative Example 2.9, Step A and Preparative Example 2.10, to Step A, the desired compound was obtained (86%).

Step C

Following a similar procedure as in Preparative Example 2, Step B, but using the product from Step B above, the desired compound was obtained (67%, MH+=331).

Preparative Example 2.11

Step A

N-Benzylpiperidone (2 g, HCl salt, hydrate) was stirred with THF (20 mL), concentrated to dryness, and placed under high vac. The residue was diluted in THF (20 mL), and methyllithium was added (2.5 eq of 1.6N in Et₂O) via syringe. After stirring for 3 hr, the mixture was concentrated in vacuo, diluted with water, extracted with CH₂Cl₂, and dried over Na₂SO₄. Filtration and concentrating in vacuo gave the desired product (50%, MH+=205).

Step B

Following a similar procedure as in Preparative Example 2, Step B, but using the product from Step A above, the title compound was obtained (95%, MH+=116).

Preparative Example 2.12

Step A

To N-benzyl-N-methylamine (20 mmol) dissolved in acetone (50 mL) was added concentrated HCl (20 mmol), paraformaldehyde (30 mmol) and 2-propanol (2 mL). After stirring at reflux overnight, the mixture was concentrated in vacuo, diluted with water, basified to pH 14 and extracted with ether. The organic phase was dried over Na₂SO₄, filtered and concentrated in vacuo to give the desired product (98%) which was used directly in Step B.

Step B

The product from Step A above (500 mg) was dissolved in MeOH (20 mL) and to this was added NaBH₄ (50 mg). After stirring for 10 min, the solution was concentrated in vacuo to give the desired compound which was used directly in Step C without purification.

Step C

The product from Step B above was diluted with MeOH (20 mL) and to this was added AcOH (0.1 mL), a catalytic amount of Pd/C (10%) and the mixture stirred under H₂ atmosphere (balloon) overnight. The mixture was filtered, 4N HCl in dioxane (1 mL) was added, and the mixture was concentrated fin vacuo to give the desired compound that was used directly without purification.

Step A

Following a similar procedure as Preparative Example 2, Step A except using methyl glycinate, the desired ester was obtained. The mixture was poured into 200 mL of 1N NaOH, then extracted with dichloromethane. The pH was adjusted to 1 and NaCl was added until saturation. After several hours, the resulting precipitate was filtered and washed with cold water to give the desired product (42%).

Step B

Following a similar procedure as in Preparative Example 2 Step B, but using the product from Step A above, the title compound was obtained (95%).

Preparative Example 2.14

Step A

Following a similar procedure as in Preparative Example 2.13, Step A except using methyl N-methylglycinate, the desired product was obtained (18%).

Step B

Following a similar procedure as in Preparative Example 2, Step B, but using the product from Step A above, the title compound was obtained (95%, MH+=225).

Preparative Example 2.16

The above n-oxide (2 g) was combined with H₂NMe/H₂O (15 cm³) and heated to 140° C. overnight. Potassium carbonate (1.3 g) added and the mixture concentrated in vacuo. Extraction with EtOH and concentration of the filtrate in vacuo gave 1.56 g of crude amine (MH+=125).

Preparative Example 3-10.50

Following the procedures set forth in Preparative Examples 1-2 but using the carboxylic acid, amine, and coupling agent [DCC (Prep. Ex. 1) or PyBrOP (Prep. Ex. 2)] listed in the Table below, the indicated amide products were obtained and used without further purification.

Product 1. Coupling Agent Prep 2. % yield Ex. Carboxylic acid Amine 3. MH⁺ 3

4

5

NH₃

6

—NH₂

7

8

9

10

10.1

10.2

10.3

10.4

10.5

10.6

10.7

10.8

10.9

10.10

10.13

10.14

10.15

10.16

10.17

10.18

10.19

10.20

10.21

10.22

10.23

10.24

10.25

10.26

10.28

10.29

10.30

10.31

10.32

10.33

10.34

10.35

10.36

10.37

10.38

10.39

10.40

10.41

10.42

10.43

10.44

10.45

10.46

10.47

10.48

10.49

10.50

Preparative Example 10.55 Alternative Procedure for Preparative Example 3

Step A

To the nitrosalicylic acid (3 g) dissolved dichloromethane (150 mL) at room temperature was added oxalyl chloride (4.3 mL) and DMF (0.01 eq.). After stirring for one day the mixture was concentrated in a vacuum to give a semi solid which was used directly in step B.

Step B

To the material from step A diluted in dichloromethane (50 mL) and cooled to 0° C. was added dimethyl amine in THF (2N solution, 24.6 mL) and triethylamine (4 eq.). After stirring for 24 hours at room temperature the mixture was concentrated in vacuo, diluted with 1M sodium hydroxide (30 mL) and after a half hour was washed with dichloromethane. The aqueous phase was acidified with 6M HCl (aq), extracted with dichloromethane and the organic phase was washed with water, dried over Na₂SO₄ and concentrated to give the title compound (3.2 g, 93%).

Step C

A mixture of the product from step B above (6 g), 10% Pd/C (0.6 g), and EtOH (80 mL) was stirred in a parr shaker under hydrogen (40 psi) at room temperature for 2 days. Filtration through celite and concentration in vacuo afforded the title product (5.1 g, 99%, MH⁺=181).

Preparative Example 11

Step A

Following a similar procedure as in Preparative Example 1 except using dimethylamine (2M in THF, 33 mL) and 5-methylsalicylic acid (5 g), the desired product was prepared (6.5 g).

Step B

Nitric acid (0.8 mL) in H₂SO₄ was added to a cooled (−20° C.) suspension of the product from Step A above (3 g) in H₂SO₄ (25 mL). The mixture was treated with 50% NaOH (aq) dropwise, extracted with CH₂Cl₂, dried over anhydrous MgSO₄, filtered and concentrated in vacuo to give the product as a crude solid (2.1 g, 44%, MH⁺=225).

Step C

The product was prepared in the same manner as described in Step B of Preparative Example 2 (0.7 g, 99%, MH⁺=195).

Preparative Example 11.1

Step A

The above amine was reacted with the acid using the procedure set forth in Preparative Example 2, Step A to yield the desired amide (54%).

Step B

Na₂S₂O₄ (1.22 g) was dissolved in water (4 ml) followed by the addition of NH₃/H₂O (300 ul). The solution was then added to the product from Step A (200 mg) in dioxane (4 ml) and stirred for 30 min. The crude material was purified via flash column chromatography (CH₂Cl₂/MeOH, 20:1) to give 100 mg of product (56%, MH+=251).

Preparative Example 11.2

Following the procedures set forth in Preparative Example 11.1, Steps A and B, but using N-methylmethoxylamine, the title compound was obtained (86%, MH+=181).

Preparative Example 11.10

Step A

Following the procedure set forth in Preparative Example 1, but using N-hydroxysuccinimide and 2% DMF in CH₂Cl₂, the desired amide was obtained (33%, MH+=297).

Step B

Following the procedure set forth in Preparative Example 2, Step B, the amine was prepared (99%, MH+=267).

Preparative Example 11.11-11.18

Following the procedures set forth in Preparative Examples 11.11 but using the carboxylic acid, amine, and coupling agent DCC indicated, the indicated amide products were obtained and used without further purification.

Prep Carboxylic 1. % Yield Ex. acid Amine Product 2. MH⁺ 11.11

1. 45, 92 2. 310.0 11.12

1. 45, 95 2. 247.2 11.13

1. 85, 85 2. 251.1 11.14

1. 99, 92 2. 211.1 11.15

1. 48, 84 2. 265 11.16

1. 78, 91 2. 238.1 11.17

1. 67, 90 2. 265.1 11.18

1. 28, 99 2. 267

Preparative Example 12

Step A

Following a similar procedure as described in Preparative Example 2 Step A except using dimethylamine in place of R-(+)-3-pyrrolidinol, the desired product was prepared.

Step B

The product from step A above (8 g) was combined with iodine (9.7 g), silver sulfate (11.9 g), EtOH (200 mL) and water (20 mL) and stirred overnight. Filtration, concentration of the filtrate, re-dissolution in CH₂Cl₂ and washing with 1M HCl (aq) gave an organic solution which was dried over anhydrous MgSO₄, filtered and concentrated in vacuo to afford the product (7.3 g, 57%, MH⁺=337).

Step C

The product from Step B above (3.1 g) was combined with DMF (50 mL) and MeI (0.6 mL). NaH (60% in mineral oil, 0.4 g) was added portionwise and the mixture was stirred overnight. Concentration in vacuo afforded a residue which was diluted with CH₂Cl₂, washed with 1M NaOH (aq), dried over anhydrous MgSO₄, filtered and concentrated in vacuo. Purification through a silica gel column (EtOAc/Hex, 1:1) gave the desired compound (1.3 g, 41%, MH⁺=351).

Step D

The product from Step D above (200 mg), Zn(CN)₂ (132 mg), Pd(PPh₃)₄ (130 mg) and DMF (5 mL) were heated at 80° C. for 48 hrs, then cooled to room temperature and diluted with EtOAc and 2M NH₄OH. After shaking well, the organic extract was dried over anhydrous MgSO₄, filtered, concentrated in vacuo and purified by preparative plate chromatography (Silica, EtOAc/Hex, 1:1) to give the desired compound (62 mg, 44%, MH⁺=250).

Step E

BBr₃ (1.3 mL, 1M in CH₂Cl₂) was added to a CH₂Cl₂ solution (5 mL) of the product from step D above (160 mg) and stirred for 30 min. The mixture was diluted with water, extracted with CH₂Cl₂, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo to give the desired compound (158 mg, MH⁺=236).

Step F

A mixture of the product from step E above (160 mg), platinum oxide (83%, 19 mg), and EtOH (20 mL) was stirred under hydrogen (25-40 psi) for 1.5 hr. Filtration through celite and concentration in vacuo afforded the product (165 mg, MH⁺=206).

Preparative Example 12.1

Step A

Following a similar procedure as in Preparative Example 2, Step A except using 3-(methylaminomethyl)pyridine and 3-nitrosalicylic acid, the desired compound was prepared (41%).

Step B

The compound from Step A above (0.3 g) was diluted with chloroform (15 mL) and stirred with mCPBA (0.4 g) for 2 hr. Purification by column chromatography (silica, 10% MeOH/CH₂Cl₂) gave the pyridyl N-oxide (0.32 g, 100%, MH⁺=303.9).

Step C

Following a similar procedure as in Preparative Example 11.1, Step B, but using the product from Step B above, the desired compound was obtained (15%, MH+=274).

Preparative Example 12.2

Step A

3-Nitrosalicylic acid (4 g) in MeOH (100 mL) and concentrated H₂SO₄ (1 mL) were stirred at reflux overnight, concentrated in vacuo, diluted with CH₂Cl₂, and dried over Na₂SO₄. Purification by column chromatography (silica, 5% MeOH/CH₂Cl₂) gave the methyl ester (2.8 g, 65%).

Step B

Following a similar procedure as in Preparative Example 2, Step B, but using the product from Step A above, the desired compound was obtained (95%, MH+=167.9).

Preparative Example 12.3

To morpholine-2-carboxitic acid (200 mg) in EtOH (40 mL) at 0° C. was added acetyl chloride (3 mL) and the mixture was stirred at reflux overnight. Concentration in vacuo, dilution with CH₂Cl₂ and washing with NaHCO₃ (aq) gave the title compound (99%, MH⁺=160.1).

Preparative Example 12.4

To N-Boc morpholine-2-carboxylic acid (2 g) in THF (5 ml) at 0° C. was added a solution of borane. THF complex (1N, 10.38 ml) and the mixture was stirred for 30 min at 0° C., and for 2 hr at room temperature. Water (200 ml) was added to the reaction and the mixture extracted with CH₂Cl₂, dried with Na₂SO₄, and concentrated in vacuo to give 490 mg of product (26%). The product was then stirred in 4N HCl/dioxane to give the amine salt.

Preparative Example 13

Step A

Following a similar procedure as in Preparative Example 1 except using dimethylamine (2M in THF, 50 mL) and 4-methylsalicylic acid (15 g), the desired compound was prepared (6.3 g, 35%).

Step B

The product from Step A above (1.5 g) was combined with iodine (2.1 g), NaHCO₃ (1.1 g), EtOH (40 mL) and water (10 mL) and stirred overnight. Filtration, concentration of the filtrate, re-dissolution in CH₂Cl₂ and washing with 1M HCl (aq) gave an organic solution which was dried over anhydrous MgSO₄, filtered and concentrated in vacuo. Purification by flash column chromatography (silica gel, 0.5-0.7% MeOH/CH₂Cl₂) gave the product (0.5 g, 20%, MH⁺=306).

Step C

Nitric acid (3.8 mL) in AcOH (10 mL) was added to the product from Step B above (0.8 g) and the mixture was stirred for 40 min. The mixture was diluted with water and extracted with CH₂Cl₂, dried over anhydrous MgSO₄, filtered and concentrated in vacuo to give the product as an orange solid (0.8 g, 92%, MH⁺=351).

Step D

A mixture of the product from step C above (800 mg), 10% Pd/C (100 mg), and EtOH/MeOH (40 mL) was stirred in a parr shaker under hydrogen (45 psi) for 1.5 hr. Filtration through celite and concentration in vacuo afforded the title product after purification by preparative plate chromatography (Silica, 10% MeOH/CH₂Cl₂, saturated with NH₄OH) to give the product (92 mg, 22%, MH⁺=195).

Preparative Example 13.1

Step A

Following a similar procedure as in Preparative Example 2, Step A except using dimethylamine (2M in THF, 23 ml) and 5-bromosalicylic acid (5 g), the desired compound was prepared (4.2 g, 75%, MH+=244).

Step B

Nitric acid (10 ml) in AcOH (100 ml) was added to the product from Step A above (2 g) and the mixture was stirred for 20 min. The mixture was diluted with water and extracted with CH₂Cl₂, dried over anhydrous MgSO₄, filtered and concentrated in to vacuo to give the product as a yellow solid (1.9 g, 80%, MH+=289).

Step C

The product from Step B above (1.9 g) was partially dissolved in EtOH (50 ml), Conc HCl in EtOH (5 ml in 40 ml), followed by SnCl₂.2H₂O (5.74 g) was added and stirred at room temperature overnight. The crude reaction was concentrated in vacuo, diluted with CH₂Cl₂ and washed with NaHCO₃, dried over anhydrous MgSO₄, filtered and concentrated in vacuo to give the product as a solid (185 mg, 9%, MH+=259).

Preparative Example 13.2

Step A

Following a similar procedure as in Preparative Example 2, Step A, except using dimethylamine (2M in THF, 29 ml) and 5-chlorosalicylic acid (5 g), the desired compound was prepared (4.5 g, 78%, MH+=200).

Step B

Nitric acid (10 ml in AcOH (100 ml) was added to the product from Step A above (2 g) and the mixture was stirred for 20 min. The mixture was diluted with water and extracted with CH₂Cl₂, dried over anhydrous MgSO₄, filtered and concentrated in vacuo to give the product as a solid (2.2 g, 88%, MH+=245).

Step C

The product from Step B above (2.2 g) was partially dissolved in EtOH (50 ml). Conc HCl in EtOH (5 ml in 40 ml), followed by SnCl₂.2H₂O (7.01 g) was added and stirred at room temperature overnight. The crude reaction was concentrated in vacuo, diluted with CH₂Cl₂ and neutralized with NaOH. The entire emulsion was filtered though celite, the layers were separated and the organic layer was dried over anhydrous MgSO₄, filtered and concentrated in vacuo to give a solid (540 mg, 22%, MH+=215).

Preparative Example 13.3

Step A

3-Nitrosalicylic acid (10 g), PyBrOP (20.52 g), and DIEA (28 ml) in anhydrous CH₂Cl₂ (200 ml) were combined and stirred at room temperature for 10 min. Dimethylamine (2M in THF, 55 ml) was added and let the reaction stir over the weekend. The mixture was extracted with 1N NaOH (aq) and the organic phase was discarded. The aqueous phase was acidified with 1N HCl (aq), extracted with CH₂Cl₂, dried over anhydrous MgSO₄, filtered and concentrated in vacuo. The oil was taken up in ether and a solid crashed out, triterated in ether to give 4.45 g of a solid (39%, MH+=211).

Step B

The product from Step A (2.99 g), K₂CO₃ (9.82 g), and iodomethane (8.84 ml) were combined in acetone and heated to reflux overnight. The reaction was filtered and concentrated in vacuo. The oil was taken up in CH₂Cl₂ and washed with 1N NaOH, dried over anhydrous MgSO₄, filtered and concentrated in vacuo to give 3.3 g of an oil (99%, MH+=225).

Step C

The crude product from Step B (3.3 g) was stirred with 10% Pd/C (350 mg) in EtOH (50 ml) under a hydrogen gas atmosphere at 20 psi overnight. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to give 2.34 g of a solid (85%, MH+=195).

Step D

The product from Step C (469 mg) was dissolved in AcOH (6 ml). 1.95M Br₂ in AcOH (1.23 ml) was added dropwise to the reaction and the mixture was stirred at room temperature for 1 hour. 50% NaOH was added to the reaction at 0° C. and the mixture was extracted with CH₂Cl₂, dried over anhydrous MgSO₄, filtered and concentrated in vacuo. The crude mixture was purified by preparative plate chromatography (Silica, 5% MeOH/CH₂Cl₂) to give the desired product (298 mg, 23%, MH+=273).

Step E

BBr₃ (2.14 ml, 1M in CH₂Cl₂) was added to a CH₂Cl₂ solution (8 ml) of the product from Step D above (290 mg) and stirred overnight. A solid formed and was filtered, taken up in MeOH/CH₂Cl₂ and purified by preparative plate chromatography (Silica, 5% MeOH/CH₂Cl₂) to give the desired product (137 mg, 49%, MH+=259).

Preparative Example 13.4

Step A

To the product from Preparative Example 13.3 Step D (200 mg) was added phenylboronic acid (98 mg), PdCl₂(PPh₃)₂ (51 mg), and Na₂CO₃ (15 mg) in THF/H₂O (4 ml/1 ml). The solution was heated at 80° C. overnight. EtOAc was added to reaction and washed with 1N NaOH. The organic layer was dried over anhydrous MgSO₄, filtered and concentrated in vacuo. The crude mixture was purified by preparative plate chromatography (5% MeOH/CH₂Cl₂) to give 128 mg of an oil (65%, MH+=271).

Step B

Following a similar procedure as in Preparative Example 13.3 Step E and using the product from Step A above, the desired compound was prepared (0.1 g, 69%, MH+=257.1).

Preparative Example 13.5-13.7

Following the procedures set forth in Preparative Example 13.4 but using the boronic acid from the Preparative Example indicated in the Table blow, the amine products were obtained.

Prep 1. Yield (%) Ex. Boronic Acid Product 2. MH⁺ 13.5

1. 15% 2. 258 13.6

1. 32% 2. 325 13.7

1. 18% 2. 325

Preparative Example 13.8

Step A

2-Cyanophenol (500 mg), sodium azide (819 mg), and triethylamine hydrochloride (1.73 g) were combined in anhydrous toluene and heated to 99° C. overnight. After the reaction cooled down, product was extracted with H₂O. Aqueous layer was acidified with conc. HCl dropwise giving a precipitate, which was filtered to give the product (597 mg, 87%, MH+=163).

Step B

Nitric acid (0.034 ml) in AcOH (5 ml) was added to the product from Step A above (100 mg) in AcOH and the mixture was allowed to stir for 1 hr. CH₂Cl₂ and H₂O were added to reaction. The organic layer was dried over anhydrous MgSO₄, filtered and concentrated in vacuo to give an oil. Trituration in ether gave the product as a solid (12 mg, 9%, MH+=208).

Step C

The product from step C (56 mg) was stirred with 10% Pd/C (20 mg) in EtOH/MeOH (15 ml) under a hydrogen gas atmosphere overnight. The reaction mixture was filtered through celite, the filtrate was concentrated in vacuo to give 29 mg of a solid (62%, MH+=178).

Preparative Example 13.9

The amine was prepared following the procedure disclosed in WO 01/68570, the disclosure of which is incorporated herein by reference thereto.

Preparative Example 13.10

The amine was prepared following the procedure disclosed in WO 01/68570, the disclosure of which is incorporated herein by reference thereto.

Preparative Example 13.11

Step A

Following the procedure described in Preparative Example 88.2, Step A, the ketone was prepared (6.4 g, 36%).

Step B

To a solution of ketone (1 g) and 2-R-methylbenzylamine (0.73 ml) in anhydrous toluene (20 ml) was added 1N TiCl₄ in toluene (3 ml) at room temperature for 1.5 hrs. The precipitate was filtered and the filtrate was concentrated in vacuo and purified via flash column chromatography (Hex/EtOAc, 18/1) to give 800 mg of product (71%).

Step C

The imine from above (760 mg) and DBU (800 ul) were stirred without solvent for 4 hr. The crude reaction was concentrated in vacuo and purified via flash column chromatography (Hex/EtOAc, 8/1) to give 600 mg of product (79%).

Step D

The imine from Step C (560 mg) was dissolved in ether (8 ml). 3N HCl (5 ml) added and let stir at room temperature overnight. The ether layer was separated and concentrated in vacuo to give 400 mg of the amine hydrochloride product (93%).

Preparative Example 13.12

The title compound was prepared similarly as in Preparative Example 13.11, but using the 2-S-methylbenzylamine instead of 2-R-methylbenzylamine (69%).

Preparative Example 13.13

Step A

At room temperature, CsF (60 mg) was added to a mixture of furfuraldehyde (1.3 ml) and TMS-CF₃ (2.5 g) and stirred at room temperature (24 h) and refluxed for another 12 h. 3N HCl (40 ml) was added and after 4 hr, the mixture was extracted with ether, washed with brine, dried over MgSO₄, and concentrated in vacuo to give the product (2.6 g, 100%).

Step B

To a solution of alcohol from above (2.6 g) in CH₂Cl₂ at room temperature was added Dess-Martin reagent (10 g) portionwise and 1 drop of water. After stirring for 3 hr at room temperature, 10% Na₂S₂O₃ (60 ml) was added and after stirring overnight, the solid was filtered off and the filtrate was extracted with CH₂Cl₂. The organic layer was washed with saturated sodium bicarbonate, dried with MgSO₄, filtered and concentrated in vacuo. Ether/hexane (1:2; 30 ml) was added to the residue, filtered, and filtrate concentrated in vacuo to give the product (2 g, 78%).

Step C

Following the procedures described in Preparative Example 13.11, Steps B, C and D, the amine salt was prepared.

Preparative Examples 13.15-13.17

Following the procedure set forth in Preparative Example 13.13, but using the prepared or commercially available aldehydes, the optically pure amine products in the Table below were obtained.

Prep Yield Ex. Aldehyde Amine Product (%) 13.15

20 13.16

31 13.17

66 13.17A

38 13.17B

31

Preparative Example 13.18

The title compound was prepared from trifluorophenylketone according to the procedures described in Preparative Example 13.11, Steps B, C, and D (68%).

Preparative Example 13.19

Step A

Methyl-3-hydroxy-4-bromo-2-thiophenecarboxylate (10.0 g, 42.2 mmol) was dissolved in 250 mL of acetone. Potassium carbonate (30.0 g, 217.4 mmol) was added followed by a solution of iodomethane (14.5 mL, 233.0 mmol). The mixture was heated to reflux and continued for 6 h. After cooled to room temperature, the mixture was filtered, the solid material was rinsed with acetone (˜200 mL). The filtrate and rinsing were concentrated under reduced pressure to a solid, further dried on high vacuum, yielding 13.7 g (100%) of methyl-3-methoxy-4-bromo-2-thiophenecarboxylate (MH⁺=251.0),

Step B

Methyl-3-methoxy-4-bromo-2-thiophenecarboxylate (13.7 g), available from step A, was dissolved in 75 mL of THF, and added with a 1.0 M sodium hydroxide aqueous solution (65 mL, 65.0 mmol). The mixture was stirred at room temperature for 24 h. A 1.0 M hydrogen chloride aqueous solution was added dropwise to the mixture until pH was approximately 2. The acidic mixture was extracted with CH₂Cl₂ (100 mL×2, 50 mL). The combined organic extracts were washed with brine (40 mL), dried with Na₂SO₄, and concentrated under reduced pressure to a solid, 10.0 g (100%, over two steps) of 3-methoxy-4-bromo-2-thiophenecarboxylic acid (MH⁺=237.0).

Step C

To a stirred solution of 3-methoxy-4-bromo-2-thiophenecarboxylic acid (6.5 g, 27.4 mmol) in 140 mL of CH₂Cl₂, obtained from step B, was added bromo-tripyrrolidinophosphonium hexafluorophosphate (PyBrOP, 12.8 g, 27.5 mmol), a 2.0 M solution of dimethyl amine in THF (34.5 mL, 69.0 mmol), and diisopropylethyl amine (12.0 mL, 68.7 mmol). After 3 d, the mixture was diluted with 100 mL of CH₂Cl₂, and washed with a 1.0 M sodium hydroxide aqueous solution (30 mL×3) and brine (30 mL). The organic solution was dried with Na₂SO₄, filtered, and concentrated to an oil. This crude oil product was purified by flash column chromatography, eluting with CH₂Cl₂-hexanes (1:1, v/v). Removal of solvents afforded a solid, further dried on high vacuum, yielding 6.76 g (93%) of N,N′-dimethyl-3-methoxy-4-bromo-2-thiophenecarboxamide (MH⁺=265.0, M+2=266.1).

Step D

An oven dried three-neck round bottom flask was equipped with a refluxing condenser, charged sequentially with palladium acetate (95 mg, 0.42 mmol), (R)-BINAP (353 mg, 0.57 mmol), cesium carbonate (9.2 g, 28.33 mmol), and N,N′-dimethyl-3-methoxy-4-bromo-2-thiophenecarboxamide (3.74 g, 14.2 mmol, from step C). The solid mixture was flushed with nitrogen. Toluene (95 mL) was added to the solid mixture followed by benzophenone imine (3.6 mL, 21.5 mmol). The mixture was heated to reflux and continued for 10 h. A second batch of palladium acetate (95 mg, 0.42 mmol) and (R)-BINAP (353 mg, 0.57 mmol) in 5 mL of toluene was added. Refluxing was continued for 14 h. The third batch of palladium acetate (30 mg, 0.13 mmol) and (R)-BINAP (88 mg, 0.14 mmol) was added, and reaction continued at 110° C. for 24 h. The mixture was cooled to room temperature, diluted with ether (50 mL), filtered through a layer of Celite, rinsing with ether. The filtrate and rinsing were concentrated under reduced pressure to an oil, which was purified twice by flash column chromatography using CH₂Cl₂ and CH₂Cl₂-MeOH (200:1) as eluents. Removal of solvents afforded 4.1 g (79%) of the amido-thiophene diphenylamine product as a solid (MH⁺=365.1).

Step E

To a stirred solution of thiophene imine (5.09 g, 13.97 mmol), obtained from step D, in 140 mL of CH₂Cl₂ at −78° C. was added dropwise a 1.0 M solution of boron tribromide in CH₂Cl₂. The mixture was stirred for 3 h while the temperature of the cooling bath was increased slowly from −78° C. to −15° C. 100 mL of H₂ was added, the mixture was stirred at room temperature for 30 min, then the two layers were separated. The organic layer (as A) was extracted with H₂O (30 mL×2). The aqueous layer and aqueous extracts were combined, washed with CH₂Cl₂ (30 mL), and adjusted to pH ˜8 using a saturated NaHCO₃ aqueous solution. The neutralized to aqueous solution was extracted with CH₂Cl₂ (100 mL×3), the extracts were washed with brine, dried with Na₂SO₄, and concentrated under reduced pressure to a light yellow solid, 1.49 g of N,N′-dimethyl-3-hydroxy-4-amino-2-thiophenecarboxamide (first crop). The previous separated organic layer A and organic washing were combined, stirred with 30 mL of a 1.0 M HCl aqueous solution for 1 h. The two layers were separated, the aqueous layer was washed with CH₂Cl₂ (30 mL) and adjusted to pH ˜8 using a saturated NaHCO₃ aqueous solution, and the separated organic layer and organic washing were combined as organic layer B. The neutralized aqueous solution was extracted with CH₂Cl₂ (30 mL×4), the extracts were washed with brine, dried by Na₂SO₄, and concentrated under reduced pressure to give 0.48 g of a solid as the second crop of the titled product. Organic layer B from above was washed with brine, and concentrated to an oil, which was separated by preparative TLC (CH₂Cl₂-MeOH=50:1) to afford 0.45 g of a solid as the third crop of the titled product. The overall yield of the product, N,N′-dimethyl-3-hydroxy-4-amino-2-thiophenecarboxamide, is 2.32 g (89%) (MH⁺=187.0).

Preparative Example 13.20

Step A

To the product from Preparative Example 13.19 Step D (1.56 g) in CH₂Cl₂ (55 ml) was added potassium carbonate (1.8 g) followed by dropwise addition of bromine (0.45 ml). After 5 hr of mixing, water (100 ml) was added to the reaction and the layers were separated. The aqueous layer was extracted with CH₂Cl₂, which was then washed with brine, saturated sodium bicarbonate, and brine again. The organic layer was dried with Na₂SO₄, and concentrated in vacuo. The residue was purified via flash column chromatography (CH₂Cl₂) to yield 1.6 g of product (83%).

Step B

The product from above was reacted in the procedure set forth in Preparative Example 13.19 Step C to give the amine.

Preparative Example 13.21

Step A

To the product from Preparative Example 13.20, Step A (300 mg) in THF (7 ml) at −78° C. was added a solution of n-BuLi (1.6M in hexanes, 0.54 ml). After 1 hr, iodomethane (0.42 ml) was added dropwise. After 3 hrs of stirring at −78° C., the reaction was warmed to room temperature overnight. Saturated ammonium chloride and water were added to the reaction and extracted with CH₂Cl₂. The organic layer was washed with saturated sodium bicarbonate and brine, dried over Na₂SO₄, and concentrated in vacuo. The crude product was purified by preparative plate chromatography (CH₂Cl₂-MeOH=70:1 to 50:1) to afford the product (111 mg, 43%).

Step B

The product from above was reacted in the procedure set forth in Preparative Example 13.19, Step E to give the amine.

Preparative Example 13.22

Step A

To the product from Preparative Example 13.19 (400 mg), Step D in CH₂Cl₂-pyridine (14 ml) was added N-chlorosuccinimide (220 mg). The mixture was stirred for 5 hr and then diluted with CH₂Cl₂ and washed with water, saturated sodium bicarbonate and brine, and concentrated in vacuo. The crude product was purified via preparative plate chromatography (CH₂Cl₂-MeOH 50:1) to give 180 mg of product (64%).

Step) B

The product from above (274 mg) was reacted in the procedure set forth in Preparative Example 13.19, Step E to give the amine (89 mg, 58%).

Preparative Example 13.23

Step A

To a stirred solution of acid (630 mg) from Preparative Example 13.19, Step B in CH₂Cl₂ (25 ml) was added oxalyl chloride (235 ul) followed by a catalytic amount of DMF (10 ul). The mixture was stirred for 1 hr, then potassium carbonate (1.8 g) was added followed by 3-amino-5-methylisoxazole (443 mg). The reaction stirred overnight and was quenched with water (25 ml). Layers were separated and the organic layer was washed with brine, dried over Na₂SO₄, and concentrated in vacuo. The crude product was purified by preparative plate chromatography (CH₂Cl₂) to afford the product (580 mg, 78%, MH+=317, 319),

Step B

The acid from the above (750 mg) step was reacted following the procedure set forth in Preparative Example 13.3, Step B to yield 625 mg of product (80%, MH+=331).

Step C

The product from above was reacted following the procedure set forth in Preparative Example 13.19, Step D to yield 365 mg of product (53%)

Step D

The product from above was reacted following the procedure set forth in Preparative Example 13.19, Step E to give the amine product (MH+=254).

Preparative Example 13.25

Step A

To a solution of 2-methylfuran (1 g) in ether (30 ml) was added n-BuLi (5.32 ml) at −78° C. The reaction was warmed to room temperature and then refluxed at 38° C. for 1 hr. The reaction was cooled back down to −78° C. where the furyl lithium was quenched with trifluorobutyraldehyde and let stir at room temperature overnight. Saturated ammonium chloride added and extracted with ether. Purified via flash column chromatography to yield pure product (2 g, 80%)

Step B

The azide was prepared using the procedure from Preparative Example 75.75, Step B and the alcohol (1 g) from above and carried on crude to Step C below.

Step C

The amine was prepared using the procedure from Preparative Example 75.75, Step C to yield 400 mg of an oil (53%).

Preparative Example 13.26

Step A

Perfluoroiodide (3.6 ml) was condensed at 78° C. Ether (125 ml) was added followed by the methyllithium.lithiumbromide complex (1.5M in ether, 18.4 ml). After 15 min, a solution of 5-methylfuraldehyde (2.5 ml) in ether was added dropwise. The reaction was warmed to −45° C. and let stir for 2 hr. Saturated ammonium chloride (30 ml) and water (30 ml) were added and let stir at room temperature for 1 hr. The layers were separated and the aqueous layer was extracted with CH₂Cl₂. The organic layer was washed with brine, dried with Na₂SO₄, filtered and concentrated in vacuo to give 5.86 g of product (100%).

Step B

The alcohol from above was reacted to form the azide using the procedure set forth in Preparative Example 75.75 Step B.

Step C

The azide from above was reacted to form the raceme amine using the procedure set forth in Preparative Example 75.75 Step C.

Preparative Example 13.27

Step A

Following the procedure set forth in Preparative Example 13.26, Step A, the alcohol was prepared (100%).

Step B

To a solution of the alcohol (500 mg) from step A above in CH₂Cl₂ (20 ml) was added N-methyl-morpholine monohydrate (575 mg) and a catalytic amount of tetrapropyl ammonium perruthenate (76 mg). After 3 hr, the mixture was diluted with hexane (10 ml) and filtered through a silica pad, rinsing with hexane: CH₂Cl₂ (200 ml). The filtrate was concentrated in vacuo to give 350 mg of product (70.7%)

Step C

The ketone (1.19 g) from Step B was dissolved in THF (9.5 ml) and cooled to 0° C. A solution of S-methyl oxazoborolidine (1M in toluene, 1 ml) followed by a solution of borane complexed with dimethylsulfide (9.5 ml, 2M in THF) was added to the solution. The mixture was stirred at 0° C. for 30 min and continued at room temperature for 5 hr. The mixture was cooled back down to 0° C. and methanol (15 ml) was added dropwise to the mixture. After 30 min, the mixture was concentrated in vacuo to give an oily residue.

The residue was dissolved in CH₂Cl₂ and washed with 1N HCl, water, and brine. Dried with Na₂SO₄, filtered and concentrated in vacuo. The crude material was purified via flash column chromatography (Hex/CH₂Cl₂, 1:1) to afford 1.14 g of an oil (67%).

Step D

The alcohol (1.14 g) from above was reacted to form the azide using the procedure set forth in Preparative Example 75.75 Step B.

Step E

The azide (1.11 g) from above was stirred with 10% Pd/C (280 mg) in EtOH (40 ml) under a hydrogen gas atmosphere overnight. The reaction was filtered through celite, the filtrate was concentrated in vacuo to give 700 mg of product (70%).

Preparative Example 13.28

Step A

To a stirred solution of 1-(2-thienyl)-1-propanone (3 g) in acetic anhydride (6 ml) at 0° C. was added dropwise a solution of fuming nitric acid in acetic acid (2 ml in 10 ml). After 30 min, the reaction was warmed to room temperature and let stir for 5 hrs where a solid precipitated out. Ice was added to the reaction and the solid was filtered. The solid was purified by flash column chromatography (Hex/CH₂Cl₂, 3:1 and 2:1) to yield 800 mg of desired product (20%).

Step B

The above nitro-thiophene compound (278 mg) was reduced using the procedure set forth in Preparative Example 2, Step B to give 54 mg of product (23%).

Step C

The above amine (395 mg), TEA (1 ml) and methanesulfonylchloride (0.5 ml) were combined in CH₂Cl₂ (35 ml) and stirred at room temperature for 1 hr. The reaction was quenched with saturated sodium bicarbonate (15 ml). The organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo to afford product (854 mg, 100%).

Step D

To the above product (854 mg) in THF (25 ml) was added dropwise a solution of tetrabutylammonium fluoride (1M in THF, 2.8 ml). The mixture was stirred overnight, then diluted with CH₂CO₂ (30 ml), washed with ammonium chloride and brine, dried over Na₂SO₄, filtered and concentrated in vacuo to afford product (2.36 g, >100%).

Step E

The ketone (2.36 g) above was reacted via the procedure set forth in Preparative Example 88.2, Step 8 to yield 547 mg of product (86.6%).

Step F

To the product from step E (310 mg) in dimethoxyethane (12 ml) was added dropwise a solution of LAH (1M in ether, 3.8 ml). The mixture was heated to reflux overnight. The reaction was cooled to room temperature, SiO₂ was added as well as water (1 ml) dropwise and let stir for 15 min. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by preparative plate chromatography (MeOH/CH₂Cl₂, 15:1) to give the amine product (40 mg, 14%).

Preparative Example 13.29

Step A

To a solution of 3-methoxythiophene (3 g) in dichloromethane (175 mL) at −78° C. was added chlorosulfonic acid (8.5 mL) dropwise. The mixture was stirred for 15 min at −78° C. and 1.5 h at room temp. Afterwards, the mixture was poured carefully into crushed ice, and extracted with dichloromethane. The extracts were washed with brine, dried over magnesium sulfate, filtered through a 1-in silica gel pad. The filtrate was concentrated in vacuo to give the desired compound (4.2 g).

Step B

The product from Step A above (4.5 g) was dissolved in dichloromethane (140 mL) and added with triethylamine (8.8 mL) followed by diethyl amine in THF (2M, 21 mL). The resulting mixture was stirred at room temperature overnight. The mixture was washed with brine and saturated bicarbonate (aq) and brine again, dried over sodium sulfate, filtered through a 1-in silica gel pad. The filtrate was concentrated in vacuo to give the desired compound (4.4 g).

Step C

The product from Step B above (4.3 g) was dissolved in dichloromethane (125 mL) and cooled in a −78° C. bath. A solution of boron tribromide (1.0 M in dichloromethane, 24.3 mL) was added. The mixture was stirred for 4 h while the temperature was increased slowly from −78° C. to 10° C. H₂O was added, the two layers were separated, and the aqueous layer was extracted with dichloro methane. The combined organic layer and extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 3.96 g of the desired hydroxy-compound.

Step D

The product from step C above (3.96 g) was dissolved in 125 mL of dichloromethane, and added with potassium carbonate (6.6 g) followed by bromine (2 mL). The mixture was stirred for 5 h at room temperature, quenched with 100 mL of H₂O. The aqueous mixture was adjusted to pH ˜5 using a 0.5N hydrogen chloride aqueous solution, and extracted with dichloromethane. The extracts were washed with a 10% Na₂S₂O₃ aqueous solution and brine, dried over sodium sulfate, and filtered through a celite pad. The filtrate was concentrated in vacuo to afford 4.2 g of the desired bromo-compound.

Step E

The product from Step D (4.2 g) was dissolved in 100 mL of acetone and added with potassium carbonate (10 g) followed by iodomethane (9 mL). The mixture was heated to reflux and continued for 3.5 h. After cooled to room temperature, the mixture was filtered through a Celite pad. The filtrate was concentrated in vacuo to a dark brown residue, which was purified by flash column chromatography eluting with dichloromethane-hexanes (1:1, v/v) to give 2.7 g of the desired product.

Step F

The product from step E (2.7 g) was converted to the desired imine compound (3 g), following the similar procedure to that of Preparative Example 13.19 step D.

Step G

The imine product from step F (3 g) was dissolved in 80 mL of dichloromethane and cooled in a −78° C. bath. A solution of boron tribromide (1.0 M in dichloromethane, 9.2 mL) was added dropwise. The mixture was stirred for 4.25 h from −78° C. to 5° C. H₂O (50 mL) was added, and the layers were separated. The aqueous layer was extracted with dichloromethane. The organic layer and extracts were combined, washed with brine, and concentrated to an oily residue. The residue was dissolved in 80 mL of methanol, stirred with sodium acetate (1.5 g) and hydroxyamine hydrochloride (0.95 g) at room temperature for 2 h. The mixture was poured into an aqueous mixture of sodium hydroxide (1.0 M aq, 50 mL) and ether (100 mL). The two layers were separated. The aqueous layer was washed with ether three times. The combined ether washings were re-extracted with H₂O once. The aqueous layers were combined, washed once with dichloromethane, adjusted to pH ˜6 using 3.0 M and 0.5 M hydrogen chloride aqueous solutions, and extracted with dichloromethane. The organic extracts were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo to give 1.2 g of desired amine compound.

Preparative Examples 13.30-13.32-A

Following the procedures set forth in Example 13.29, but using commercially available amines, hydroxy-amino-thiophene products in the Table below were obtained.

Yield (%) Prep Ex. Amine Product MH⁺ 13.30 (Bn)₂NH

10% 375.1 13.31 Me(Bn)NH

14% 299.0 13.32 Et(Bn)NH

22% 13.32A (Et)₂NH

25%

Preparative Example 13.33

Step A

2-Chlorosulfonyl-3-methoxy-thiophene (4.0 g, 18.8 mmol), the product from Step A of Preparative Example 13.29 was converted to 3-methoxy-2-ethylbenzylsulfonyl-thiophene (5.5 g, 94%, MH⁺=312.1) by using ethylbenzyl-amine, following the procedure set forth in Preparative Example 13.29, Step B.

Step B

The product from Step A above (5.5 g, 17.70 mmol) was demethylated following the procedure set forth in Preparative Example 13.29, Step C. The alcohol product was obtained in 4.55 g (87%, MH⁺=298.0).

Step C

The product from Step B above (4.55 g, 15.30 mmol) was brominated using the procedure set forth in Preparative Example 13.29, Step D. The corresponding bromide was obtained in 4.85 g (84%).

Step D

The bromo-alcohol from Step C above (4.84 g, 12.86 mmol) was methylated using the procedure set forth in Preparative Example 13.29, Step E. The product was obtained in 4.82 g (96%).

Step E

The product from Step D above (4.82 g, 12.36 mmol) was stirred with concentrated sulfuric acid (5 mL) at room temperature for 3 h. Ice water (30 mL) was added to the mixture followed by CH₂Cl₂ (50 mL). The aqueous mixture was adjusted to pH ˜6 using a 1.0 M NaOH aqueous solution. The layers were separated. The aqueous layer was extracted with CH₂Cl₂ (50 mL×3). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated to a dark brown oil, which was purified by flash column chromatography, eluting with CH₂Cl₂-hexanes (1:1, v/v). Removal of solvents afforded 3.03 g (82%) of the debenzylated product (M⁺=300.0, M+2=302.0).

Step F

The product from Step E (1.34 g, 4.45 mmol) was methylated using the procedure set forth in Preparative Example 13.29, Step E. The desired product was obtained in 1.36 g (97%, M⁺=314.1, M+2=316.0).

Step G

The product from Step F (1.36 g, 4.33 mmol) was converted to imine product (1.06 g, 55%, MH⁺=415.1) using the procedure set forth in Preparative Example 13.29, Step F.

Step H

The imine product from Step G (1.06 g, 2.56 mmol) was converted to the desired hydroxy-amino thiophene compound (0.26 g, 43%) using the procedure set forth in Preparative Example 13.29, Step G.

Preparative Example 13.34

Step A

2-Chlorosulfonyl-3-methoxy-thiophene (3.8 g, 17.87 mmol), the product from step A of Preparative Example 13.29, was dissolved in 100 mL of CH₂Cl₂ and 20 mL of pyridine. 3-Amino-5-methyl-isoxazole (3.5 g, 35.68 mmol) was added. The mixture was stirred for 20 h at room temperature, diluted with 100 mL of CH₂Cl₂, and washed with a 0.5 N HCl aqueous solution (50 mL×2), H₂O (50 mL), and brine (50 mL). The organic solution was dried with Na₂SO₄, and concentrated in vacuo to a brown oil. This oil was dissolved in 100 mL of CH₂Cl₂, washed again with a 0.5 M HCl aqueous solution (30 mL×3) and brine. After dried over Na₂SO₄, the organic solution was concentrated in vacuo to a yellow solid, 4.48 g (91%, MH⁺=275.0) of the desired product.

Step B

The product from Step A above (4.48 g, 16.33 mmol) was dissolved in acetone (100 mL), added with potassium carbonate (5.63 g, 40.80 mmol) and iodomethane (10.1 mL, 163.84 mmol). The mixture was stirred at room temperature for 1.5 h, diluted with 100 mL of hexanes and 50 mL of CH2Cl2, and filtered through a 1-in silica gel pad, rinsing with CH2Cl2. The filtrate was concentrated under reduced pressure to give 4.23 g (90%, MH⁺=289.0) of the desired product as a light yellow solid.

Step C

To a stirred suspension of sodium hydride (130 mg, 95%, 5.4 mmol) in 8 mL of N,N′-dimethylformamide at room temperature was added ethanethiol (0.45 mL, 6.0 mmol) dropwise. After 5 min, the mixture became a clear solution, and was added to a stirred solution of the product obtained from Step B above (0.45 g, 1.56 mmol) in 2 mL of N,N′-dimethylformamide in a round bottom flask. The flask was seated with a ground glass stopper, and the mixture was heated at 90-95° C. for 4 h. After cooled to room temperature, the mixture was poured into 20 mL of a 1.0 M NaOH aqueous solution, further rinsed with 20 mL of H₂O. The aqueous mixture was washed with diethyl ether (30 mL×2), adjusted to PH ˜5 using a 0.5 M HCl aqueous solution, and extracted with CH₂Cl₂ (50 mL×4). The combined extracts were washed with brine, dried (Na₂SO₄), and concentrated to a dark yellow solution. This was dissolved in 50 mL of ethyl acetate, washed with H₂O (30 mL×2) and brine (30 mL), dried over Na₂SO₄. Evaporation of solvent gave 0.422 g of the alcohol product (99%, MH⁺=275.0).

Step D

The alcohol obtained from Step C above (0.467 g, 1.70 mmol) was brominated using the procedure set forth in Preparative Example 13.29, Step D, to afford the corresponding bromide in 0.607 g (100%).

Step E

The bromide obtained from Step D above (0.607 g, 1.72 mmol) was methylated using the procedure set forth in Preparative Example 13.29, Step F, to give the desired product in 0.408 g (65%, M⁺=367, M+2=369.1).

Step F

The product (0.405 g, 1.103 mmol) from Step E above was converted to the imine compound (0.29 g, 56%) using the procedure set forth in Preparative Example 13.29, Step F.

Step G

The imine product obtained from Step F above (0.29 g, 0.61 mmol) was demethylated using the procedure set forth in Step C above to give the corresponding alcohol as a dark yellow oil, which was dissolved in 5 mL methanol and added with sodium acetate (0.12 g, 1.46 mmol) and hydroxyamine hydrochloride (0.075 g, 1.08 mmol). The resulting mixture was stirred at room temperature for 3 h, and poured into 10 mL of 1.0 M NaOH aqueous solution. 30 mL of H₂O was used as rinsing and combined to the aqueous layer. The aqueous mixture was washed with diethyl ether (40 mL×3), adjusted to pH 6 using a 1.0 M HCl aqueous solution, and extracted with ethyl acetate (40 mL×3). The organic extracts were washed with H₂O (20 mL×2), brine (20 mL), dried over Na₂SO₄, and concentrated in vacuo to give 0.112 g of the desired hydroxy-amino thiophene sulfonamide (64%, MH⁺=290).

Preparative Example 13.35

Step A

To a solution of 2-methyl furan (1.72 g) in ether was added BuLi (8.38 mL) at −78° C. and stirred at room temperature for half an hour. The reaction mixture again cooled to −78° C. and quenched with cyclopropyl amide 1 and stirred for two hours at −78° C. and slowly warmed to room temperature. The reaction mixture stirred for three hours at room temperature and quenched with the addition of saturated ammonium chloride solution. The mixture was taken to a separatory funnel, washed with water, brine and dried over anhydrous sodium sulfate. Filtration and removal of solvent afforded the crude ketone, which was purified by using column chromatography to afford the ketone 3.0 g (87%) as a pale yellow oil

Step B

To a solution of ketone (1.0 g) in THF (5.0 mL) at 0° C. was added R-methyl oxazoborolidine (1.2 Ml, 1M in toluene) dropwise followed by addition of a solution of borane complexed with dimethyl sulfide (1.85 mL, 2M in THF). The reaction mixture was stirred for 30 minutes at 0° C. and than at room temperature for one hour. The reaction mixture was cooled to Cc and MeOH was added carefully. The mixture was stirred for 20 minutes and was concentrated under reduced pressure. The residue was extracted with ether, washed with water, 1M HCl (10 mL), saturated sodium bicarbonate (10.0 mL) water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and removal of solvent afforded the crude alcohol which was purified by silica gel chromatography to afford the pure alcohol 0.91 g (91%) as yellow oil.

Preparative Example 13.36

Step A

An equimolar mixture of 2-methylfuran (1.0 g) and anhydride (2.6 g) was mixed with SnCl₄ (0.05 mL) and heated at 100° C. for 3 hours. After cooling the reaction mixture, water (10 mL) was added, followed by saturated sodium carbonate solution until it becomes alkaline. The reaction mixture was extracted with ether several times and the combined ether layer was washed with water, brine and dried over anhydrous sodium sulfate. Filtration and removal of solvent afforded the crude ketone, which was purified by using silica gel chromatography to afford the ketone 0.9 g (43%) as a yellow oil.

Step B

The step B alcohol was obtained following a similar procedure set forth in the preparative example 13.35 Step B.

Preparative Example 13.37

Step A

To a solution of 5-methyl furan-2-aldehyde (1.0 g) and 3-bromo-3,3-difluoropropene (2.24 g) in DMF (30 mL) was added indium powder (1.66 g) and lithium iodide (50.0 mg). The reaction mixture was stirred over night, diluted with water and extracted with ether. The ether layer was washed with water, brine and purified by silica gel chromatography to afford the pure alcohol 2.8 g (92%).

Preparative Examples 13.38-13.45

Following a similar procedure set forth in Preparative Examples 13.25 and 13.35, and using the indicated Furan and Electrophile, the following Alcohols in the Table below were prepared.

Prep. ex Furan Electrophile Alcohol Yield 13.38

86% 13.39

69% 13.40

84% 13.41

82% 13.42

60% 13.43

65% 13.44

82% 13.45

89%

Preparative Examples 13.50-13.61

Following a similar procedure set forth in Preparative Examples 13.25, and using the indicated Alcohol, the following Amines in the Table below were prepared.

PREP. EX. ALCOHOL AMINE % YIELD 13.50 13.45

28% 13.51 13.38

58% 13.52 13.36

69% 13.53 13.35

81% 13.54 13,37

82% 13.55 13.39

45% 13.56 13.41

57% 13.57 13.40

58% 13.58 13.44

54% 13.59 13.42

53% 13.60 13.43

50% 13.61 13.37

82%

Preparative Example 13.70

Step A

The imine was prepared following the procedure set forth in the preparative example 13.19 from the known bromoester (10 g) as a yellow solid, Step A to yield 1.1 g (79%).

Step B

The Step A product (0.69) was reacted following the procedure set forth in the preparative example 13.19 to give the amine product 0.19 g (64%).

Step C

The Step B product (1.0) was reared following the procedure set forth in the preparative example 13.19 to give the acid as yellow solid 0.19 g (94%).

Step D

The Step A product (0.36 g) was reacted following the procedure set forth in the preparative example 13.19 to give the amino acid as yellow solid 0.167 g (93%).

Preparative Example 13.71

Following a similar procedure set forth in Preparative Example 13.33 Step E, but using the product from Preparative Example 13.32, the title compound was obtained (121 mg, 69% yield, MH+=223.0).

Preparative Example 14

Step A

3-Nitro-1,2-phenylenediamine (10 g), sodium nitrite (5.4 g and acetic acid (20 mL) were heated at 60° C. overnight, then concentrated in vacuo, diluted with water and extracted with EtOAc. The product precipitated from the organic phase (5.7 g) as a solid and used directly in step B.

Step B

The product from Step A above (2.8 g) was stirred with 10% Pd/C (0.3 g) in MeOH (75 mL) under a hydrogen gas atmosphere overnight. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo to give the product (2.2 g, MH+=135).

Preparative Example 15

Step A

N-methyl-4-bromopyrazole-3-carboxylic acid was prepared according to known methods, see. Yu, A. M.; Andreeva, M. A.; Perevalov, V. P.; Stepanov, V. I.; Dubrovskaya, V. A.; and Seraya, V. I. in Zh. Obs. Khim, (Journal of General Chemistry of the USSR) 1982, 52, 2592 (and the references cited therein) the disclosure of which is incorporated herein by reference thereto.

Step B

To a solution of N-methyl-4-bromopyrazole-3-carboxylic acid (2.0 g), available from step A, in 65 mL of anhydrous DMF was added bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP, 4.60 g), dimethyl amine (10 mL, 2.0 M in THF) and diisopropylethyl amine (5.2 mL) at 25° C. The mixture was stirred for 26 h, and concentrated under reduced pressure to an oily residue. This residue was treated with a 1.0 M NaOH aqueous solution, and extracted with ethyl acetate (50 mL×4). The organic extracts were combined, washed with brine, and dried with anhydrous Na₂SO₄. Removal of solvents yielded an oil, which was purified by preparative thin layer chromatography, eluting with CH₂Cl₂-MeOH (20:1), to give 1.09 g of the amide product (48%, MH⁺=232.0).

Step C

To a solution of the amide (0.67 g), obtained from step B, in 8 mL of concentrated sulfuric acid at 0° C. was added potassium nitrate (1.16 g) in small portions. The cooling bath was removed and the mixture was heated at 110° C. for 6 h. After cooling to 25° C., the mixture was poured into 80 mL of H₂O, and an additional 20 mL of H₂O was used as a rinse. The aqueous mixture was extracted with CH₂Cl₂ (100 mL×4). The combined extracts were washed with brine (50 mL), sat. NaHCO₃ aqueous solution (50 mL), brine (50 mL), and dried with Na₂SO₄. Evaporation of solvent gave an oil, which solidified on standing. The crude product was purified by flash column chromatography, eluting with CH₂Cl₂-MeOH (1:0, 50:1 and 40:1). Removal of solvents afforded 0.521 g (65%) of the product as a solid (MH⁺=277.1)

Step D

The product (61 mg) obtained from step C was dissolved in 3 mL of THF. To this solution at −78° C. was added dropwise along the inside wall of the flask a 1.6 M solution of n-butyl lithium in hexane. After 45 min, a solution of methyl borate (0.1 mL) in THF (1.0 mL) was added. After 1.5 h, a solution of acetic acid in THF (0.25 mL, 1:10 v/v) was added to the cold mixture. Stirring was continued for 10 min, and a 30 wt % aqueous hydrogen peroxide solution (0.1 mL) was added. An additional portion of hydrogen peroxide aqueous solution (0.05 mL) was added 20 min later. The cooling bath was removed, and the mixture was stirred at 25° C. for 36 h. The mixture was poured into 30 mL of H₂O, and the aqueous mixture was extracted with ethyl acetate (30 mL×4). The extracts were combined, washed with brine (10 mL), 5% NaHCO₃ aqueous solution (10 mL) and brine (10 mL). The organic layer was dried with Na₂SO₄ and concentrated under reduced pressure to a residue, which was then purified by preparative thin layer chromatography eluting with CH₂Cl₂-MeOH (20:1) to give the hydroxylated product (5 mg, 10%, MH⁺=215.3).

Step E

By treating the hydroxylated product of Step E with H₂ under the conditions of 10% palladium on carbon in ethanol, one would obtain the desired hydroxyl-amino compound.

Preparative Example 16

Step A

Following a similar procedure used in Preparative Example 13, Step C except using the known compound, 4-methyl-pyrimidin-5-ol, the product can be prepared.

Step B

Following a similar oxidation procedure used in Preparative Example 15, Step A except using the compound from Step A above, the product can be prepared.

Step C

Following a similar procedure used in Preparative Example 11, Step A except using the compound from Step B above, the product can be prepared.

Step D

Following a similar procedure used in Preparative Example 12, Step F except using the compound from Step C above, the product can be prepared.

Preparative Example 17

Step A

Following a similar procedure used in Preparative Example 11, Step A except using the known 4-hydroxynicotinic acid, the product can be prepared.

Step B

Following a similar procedure used in Preparative Example 13, Step C except using the compound from Step A above, the product can be prepared.

Step C

Following a similar procedure used in Preparative Example 12, Step F except using the compound from Step C above, the product can be prepared.

Preparative Example 18

Step A.

Following a similar procedure used in Preparative Example 13, Step C except using the compound from Step A above, the product can be prepared.

Step B

Stirring the compound from Step A above, a suitable Pt or Pd catalyst and EtOH under hydrogen atmosphere (1-4 atm) the product can be prepared.

Preparative Example 19

The amine was prepared following WO 01/68570, the disclosure of which is incorporated herein by reference thereto.

Preparative Example 19.1

The amine was prepared following WO 01/68570, the disclosure of which is incorporated herein by reference thereto.

Preparative Example 20

The title compound was prepared according to the procedure set forth in Preparative Example 1, but instead using 4-nitrosalycilic acid (57%, MH+=181).

Preparative Example 22.1

3,4-Diethoxy-1,2-5-thiadiazole-1,1-oxide (226 mg, 1.4 mmol) (prepared according to known methods, see: J. Am. Chem. Soc., 1982, p. 1375, the disclosure of which is incorporated herein by reference thereto) was added to 3-amino-2-hydroxy-N,N-dimethylbenzamide (252 mg, 1.4 mmol) in methanol (15 mL). The reaction mixture was stirred overnight. The desired product precipitated and was recovered by filtration. Concentration of the mother liquor to half volume afforded a second batch of precipitated product. Combined batches afforded 293 mg (65% yield) of product with sufficient purity to be used in subsequent steps. MH⁺=346.9.

Preparative Example 22.2

3,4-Diethoxy-1,2-5-thiadiazole-1,1-oxide (226 mg, 1.4 mmol) (prepared according to known methods, see: J. Am. Chem. Soc., 1982, p. 1375, the disclosure of which is incorporated herein by reference thereto) was added to R-2-phenylpropylamine (0.195 mL, 1.4 mmol) in methanol (15 mL). The reaction mixture was stirred overnight. Evaporation of solvent afforded an amorphous solid (390 mg, 99%) of sufficient purity for use in subsequent steps. MH⁺=279.9.

Preparative Examples 22.3-22.7

Following a similar procedure set forth in Preparative Example 22.1 but using the commercially available (or prepared amine) indicated in the Table below, the following thiadiazoleoxide intermediates could be obtained.

Ex. Amine Product 22.3

22.4

22.5

22.6

22.7

Preparative Examples 22.8-22.38

Following a similar procedure as that set forth in Preparative Example 22.1 but using the commercially available (or prepared amine) indicated in the Table below, the following thiadiazoleoxide intermediates could be obtained.

Ex. Amine Product 22.8

22.9

22.10

22.16

22.17

22.19

22.20

22.21

22.22

22.23

22.24

22.25

22.26

22.27

22.28

22.29

22.30

22.31

22.32

22.34

22.36

22.37

22.38

Preparative Examples 22.39-22.51

Following a similar procedure set forth in Preparative Example 22.1 but using the commercially available (or prepared amine) indicated in the Table below, the following thiadiazoleoxide intermediates could be obtained.

Ex. Amine Product 22.39

22.40

22.41

22.42

22.43

22.44

22.45

22.46

22.47

22.48

22.49

22.50

22.51

Preparative Examples 23.1-23.10

Following a similar procedure set forth in Preparative Example 22 but using the commercially available (or prepared amine) from the Preparative Example indicated in the Table below, the following thiadiazoleoxide intermediates were obtained.

Prep 1. Yield Ex Amine Product 2. MH+ 23.1

1. 99% 2. 379 23.2

used crude 23.3

used crude 23.8

1. 85% 2. 390.0 23.9

1. 25% 23.10

1. 83% 2. 277.1

Preparative Examples 23.4-23.2

Following a similar procedure set forth in Preparative Example 22 but using the commercially available (or prepared amine) from the Preparative Example indicated in the Table below, the following thiadiazoleoxide intermediates could be obtained.

Prep Ex Amine Product 23.4

23.5

23.6

23.7

Preparative Example 23.10A

Following a similar procedure as that used in the Preparative Example 1302 Steps A-C, except using pyrrolidine in Step A instead of diethyl amine and 50 psi hydrogen pressure in the hydrogenation Step C, the title compound was obtained (80%, 1.0 g, MH⁺=243.1)

Preparative Example 23.108

Following the same procedure set forth in the Preparative Example 23.10A, except by using 30 psi hydrogen pressure in the hydrogenation Step C, the title compound was obtained (83%, 1.2 g, MH⁺=277.1).

Preparative Example 24

Step A

To a solution of N-protected amino acid (1.5 g, 6.9 mmol) in CH₂Cl₂ (25 mL) at room temperature was added DIPEA (3.6 mL, 20.7 mmol), and PyBrOP (3.4 g, 6.9 mmol) followed by MeNH₂ (6.9 mL, 13.8 mmol, 2.0 M in CH₂Cl₂). The resulting solution was stirred for 18 h at room temperature (until TLC analysis deemed the reaction to be complete). The resulting mixture was washed sequentially with 10% citric acid (3×20 mL), sat. aq. NaHCO₃ (3×20 mL), and brine (3×20 mL). The organic layer was dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography eluting with CH₂Cl₂MeOH (40:1) to afford 1.0 g (63% yield) of a solid.

Step B

To a round bottom charged with the N-protected amide (1.0 g, 4.35 mmol) (from Step A) was added 4N HCl/dioxane (10 mL) and the mixture was stirred at room temperature for 2 h. The mixture was diluted with Et₂O (20 mL) and concentrated under reduced pressure. The crude product was treated with Et₂O (2×20 mL) and concentrated under reduced pressure to afford 0.72 g (˜100% yield) of crude product as the HCl salt. This material was taken on without further purification or characterization.

Preparative Examples 25-33.1

Following the procedure set forth in Preparative Example 24 but using the commercially available N-protected amino acids and amines in the Table below, the amine hydrochloride products were obtained.

Prep Yield Ex. Amino acid Amine Product (%) 25

NH₃

70 26

71 27

66 28

65 29

90 30

68 31

68 32

97 33

97 33.1

20

Preparative Example 33.2

Step A

BOC-valine (45 mg) and PS-carbodiimide (200 mg) were suspended in CH₂Cl₂ (4 ml). After addition of the CH₂Cl₂-amine solution (0.138N, 1 ml), the mixture was shaken overnight. The solution was filtered and the resin was washed with more CH₂Cl₂, and the filtrate was concentrated in vacuo to yield the product, which was carried on directly in Step B.

Step B

The crude material from Step A was dissolved in 4N HCl/dioxane (2.5 ml) and stirred for 2 h. The reaction was concentrated in vacuo to yield the desired amine hydrochloride, which was used directly in the next step,

Preparative Examples 33.3-33.47

Following the procedure set forth in Example 33.2 but using the commercially available N-protected amino acids in the Table below, the amine hydrochloride products were obtained.

Prep Ex. Amino acid Amine Product 33.3

33.4

33.5

33.6

33.7

33.8

33.9

33.10

33.11

33.12

33.13

33.14

33.15

33.16

33.17

33.18

33.19

33.20

33.21

33.22

33.23

33.24

33.25

33.26

33.27

33.28

33.29

33.30

33.31

33.32

33.33

33.34

33.35

33.36

33.37

33.38

33.39

33.40

33.41

33.42

33.43

33.44

33.45

33.46

33.47

Preparative Example 34

To a solution of 3-chlorobenzaldehyde (2.0 g, 14.2 mmol) in THF (5 mL) at 0° C. was added LiN(TMS)₂ (17.0 ml, 1.0 M in THF) dropwise and the resulting solution was stirred for 20 min. EtMgBr (6.0 mL, 3.0 M in Et₂O) was added dropwise and the mixture was refluxed for 24 h. The mixture was cooled to room temperature, poured into saturated aqueous NH₄Cl (50 mL), and then extracted with CH₂Cl₂ (3×50 volumes). The organic layers were combined, concentrated under reduced pressure. The crude residue was stirred with 3 M HCl (25 mL) for 30 min and the aqueous layer was extracted with CH₂Cl₂ (3×15 mL) and the organic layers were discarded. The aqueous layer was cooled to 0° C. and treated with solid NaOH pellets until pH=10 was attained. The aqueous layer was extracted with CH₂Cl₂ (3×15 mL) and the organic layers were combined. The organic layer was washed with brine (1×25 mL), dried (Na₂SO₄), and concentrated under reduced pressure to afford 1.6 g (66% yield) of the crude amine as an oil (MH⁺ 170). This material was determined to be >90% pure and was used without further purification.

Preparative Example 34.1

The aldehyde (3.5 g) and conc. HCl (20 ml) were combined and stirred overnight at 40° C. The reaction mixture was poured into cold water and extracted with ether, washed with satd. NaHCO₃ and brine, dried over anhydrous MgSO₄, filtered and concentrated in vacuo to give 1.76 g of product (55%)

Preparative Example 34.2

Chlorine was bubbled into 100 ml of CH₂Cl₂ at 10° C. The aldehyde (3.73 ml) was charged with 50 ml of CHCl₃ and then cooled to 0° C. AlCl₃ was added portionwise, followed by the chlorine solution and let stir at room temperature overnight. The reaction was poured into 150 ml of ice and 50 ml of 3N HCl and stirred for 30 min. Organic layer was washed with brine, dried with Na₂SO₄, and concentrated in vacuo. The crude product was purified via flash column chromatography (Hex/EtOAc 40/1) to yield 1.5 g of pure product.

Preparative Example 34.3

Step A

The ketone (3.25 g) was reacted following the procedure set forth in Preparative Example 88.2, Step B to give the oxime (3.5 g, 99%).

Step B

The product from step A (1.2 g) was stirred with AcOH (3 ml) and Pd/C (10%, 300 mg) in EtOH (40 ml) under a hydrogen atmosphere overnight. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The crude material dissolved in ether and washed with 2N NaOH, organic washed with brine, dried with Na₂SO₄, and concentrated in vacuo to give product (960 mg, 86%).

Preparative Example 34.4

Step A

To a suspension of NaH (1.45 g) in DMF (25 ml) under a nitrogen atmosphere was added p-bromophenol (5 g) at 0° C. After stirring for 20 min, BrCH₂CH(OEt)₂ (5.3 ml) was added and the reaction was heated to reflux overnight. The solution was cooled and poured into ice water (80 ml) and extracted with ether. The ether layer was washed with 1N NaOH and brine, dried with MgSO₄, filtered and concentrated in vacuo to give 8.4 g of crude product (100%)

Step B

To a solution of the product from Step A (8.4 g) in benzene (50 ml) was added polyphosphoric acid (10 g). The mixture was heated at reflux for 4 hrs. The reaction was cooled to 0° C. and poured into ice water (80 ml) and extracted with ether. The ether layer was washed with saturated sodium bicarbonate and brine, dried with MgSO₄, filtered and concentrated in vacuo to give 4.9 g of crude product (85%)

Step C

To a solution of the product from Step B (2 g) in ether (20 ml) at −78° C. was added t-BuLi dropwise. After stirring for 20 min, DMF (950 mg) was added dropwise and the mixture was stirred at −25° C. for 3 hrs and then warmed to room temperature overnight. Saturated ammonium chloride was added and the solution was extracted with ether. The ether layer was washed with brine, dried with MgSO₄, filtered and concentrated in vacuo to give 980 mg of crude product (67%).

Step D

To a solution of aldehyde (400 g) in ether (10 ml) was added LiN(TMS)₂ (1M in THF, 3.3 ml) at 0° C. dropwise. The solution was stirred at 0° C. for 30 min and EtMgBr (3M in THF, 1.83 ml) was added dropwise. The reaction was refluxed overnight, cooled to 0° C., quenched with saturated ammonium chloride and extracted with ether. The ether was stirred with 3N HCl (20 ml), then the aqueous layer was basified with NaOH pellets and extracted with ether. The ether layer was washed with brine, dried with MgSO₄, filtered and concentrated in vacuo to give 220 mg of product (46%).

Preparative Example 34.5

Following the procedures set forth in Preparative Example 34.4 Steps A through D, but using m-bromophenol (8 g), both amines were formed and separated by preparative plate chromatography (63-65%, MH+=175).

Preparative Example 34.6

To a solution of 3-methyl-thiophene (5 g) in ether (5 ml) was added dropwise a solution of n-BuLi (1.6M in hexane, 32 ml). The mixture was stirred for 1.5 hr at room temperature. DMF (5.1 ml) was then added and let stir overnight. The mixture was poured into saturated ammonium chloride and extracted with ether. The ether layer was washed with brine, dried with Na₂SO₄, and concentrated in vacuo. The crude product was purified via flash column chromatography (EtoAc/Hex 20:1) to afford 5.27 g of an oil (84%).

Preparative Example 34.7

Step A

To a solution of 4-bromo-2-furaldehyde (4 g) in MeOH (75 ml) was added trimethyl-orthoformate (3.8 ml). A catalytic amount of p-toluene sulfonic acid (195 mg) and the mixture was heated to reflux for 3.5 hr. The reaction was cooled down and potassium carbonate was added. The mixture was filtered through a silica gel pad. The filtrate was concentrated in vacuo, dissolved in CH₂Cl₂ and filtered. The filtrate was again concentrated in vacuo to give 4.03 g of product (80%).

Step B

To a solution of the product from Step A (2.02 g) in THF (80 ml) at −78° C. was added dropwise a solution of n-BuLi (2.5M in hexanes, 4.4 ml) and stirred for 1.5 hr. A solution of iodomethane (1.7 ml) was added and let stir for 2.5 hrs at 60° C. The cooling bath was removed and saturated ammonium chloride was added and let stir for 10 min. The layers were separated and the organic layer was washed with brine, dried with Na₂SO₄, and concentrated in vacuo to afford 1.34 g of crude product,

Step C

The product from Step B (1.43 g) was dissolved in acetone (50 ml) and treated with a catalytic amount of p-toluene sulfonic acid (80 mg). The mixture was heated to reflux for 2 hr. The reaction was cooled down and solid potassium carbonate was added. The mixture was filtered through a silica gel pad and the filtrate was concentrated in vacuo to give 1.246 g of crude product.

Preparative Example 34.8

Step A

To a stirred solution of potassium t-butoxide (2.5 g) in HMPA (20 ml) was added 2-nitropropane (2 ml) dropwise. After 5 min, a solution of methyl-5-nitro-2-furoate (3.2 g) in HMPA (8 ml) was added to the mixture and stirred for 16 hr. Water was added and the aqueous mixture was extracted with EtOAc. The EtOAc layer was washed with water, dried with MgSO₄, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography (Hex/EtOAc, 6:1) to yield 3.6 g of product (90%).

Step B

To a solution of the product from Step A (3.6 g) in toluene (16 ml) was added tributyltin hydride (5.4 ml) followed by AlBN (555 mg). The mixture was heated to 85° C. for 3.5 hr. After cooling, the mixture was separated by flash column chromatography (Hex/EtOAc, 7:1) to afford 2.06 g of product (73%).

Step C

To a solution of product from Step B (2.05 g) in THF (60 ml) at 0° G was added a solution of LAH (1M in ether, 12.8 ml). The reaction was stirred at room temperature for 30 min. Water and 1M NaOH was added until a precipitate formed, diluted with EtOAc, stirred for 30 min and then filtered through a celite pad. The organic filtrate was concentrated in vacuo to give 1.56 g of product (93%).

Step D

To a solution of product from Step C (2.15 g) in CH₂Cl₂ (100 ml) was added Dess-Martin oxidant (7.26 g) in CH₂CO₂ (45 ml) and stirred for 30 min. The mixture was diluted with ether (200 ml). The organic layer was washed with 1N NaOH, water and brine, dried with MgSO₄, filtered and concentrated in vacuo to give oil and solid. The material was extracted with ether and filtered. Some solid crystallized out from the filtrate, filtered again, and the filtrate was concentrated in vacuo to give 2.19 g of product.

Preparative Example 34.9

Step A

To a solution of carboxylic acid (5 g) in CH₂Cl₂ (400 ml) at 0° C. was added N(OCH₃)CH₃HCl (11.59), DEC (15.1 g), HOBt (5.3 g) and NMM (43 ml) and stirred for 14 hr. The mixture was diluted with CH₂Cl₂ (100 ml) and the organic layer was washed with 10% HCl, saturated sodium bicarbonate and brine, dried with Na₂SO₄, and concentrated in vacuo to afford 5.74 g of crude product (85%).

Step B

To a solution of iodoethane (0.56 ml) in ether (5 ml) at −78° C. was added a solution of t-BuLi (1.7M in pentane, 8.3 ml) dropwise. The mixture was warmed to room temperature for 1 hr and transferred to a 100 ml round bottom charged with the product from Step A (1 g) in THF (12 ml) at −78° C. The mixture was stirred at −78° C. for 1 hr and at 0° C. for an additional 2 hr. 1M HCl was added dropwise followed by CH₂Cl₂. The layers were separated and the organic layer was washed with brine, dried with Na₂SO₄, and concentrated in vacuo to afford 620 mg of product (76%).

Step C

To a solution of the product from Step B (620 mg) in THF/MeOH (10:1) at 0° C. was added NaBH₄ (250 mg) in one portion. The mixture was stirred overnight at 0° C., concentrated in vacuo and the crude material was dissolved in CH₂Cl₂ and washed with 1N NaOH and brine, dried with Na₂SO₄, and concentrated in vacuo to afford 510 mg of product.

Step D

The above material was reacted in the procedures set forth in Preparative Example 75.75 Steps B and C to yield 170 mg of amine product (28%).

Preparative Example 34.10

The above amine was made analogous to the procedures set forth in Patent WO96/22997 p. 56 (the disclosure of which is incorporated herein by reference thereto), but using ethylglycine instead of benzylglycine in the DCC coupling.

Preparative Example 34.11

Step A

To the nitro compound (3.14 g) and cyclohexylmethanol (1.14 g) in THF (50 ml) was added PPH₃ (4.72 g) and cooled to 0° C. Diisopropylazadicarboxylate (3.15 ml) was added dropwise and let stir overnight. The reaction was concentrated in vacuo and purified via flash column chromatography (Hex/EtOAc, 30.1) to give product (3.3 g), which was carried on directly to the next step.

Step B

To the product from step A (3.3 g) in EtOH (50 ml) was added 10% Pd/C (1.7 g) under a hydrogen atmosphere at 55 psi and let stir overnight. The reaction was filtered through celite and concentrated in vacuo to give 3.2 g of product.

Preparative Example 34.12

Step A

A solution of acid (2 g) in ether (20 ml) was added dropwise to a suspension of LiAlH₄ (350 mg) in ether (15 ml) at 0° C. The solution was refluxed for 3 hr and stirred at room temperature overnight. 5% KOH was added and reaction was filtered, extracted with ether, dried with MgSO₄, filtered and concentrated in vacuo to give the product (1.46 g, 79%, MH+=166).

Step B

To a solution of alcohol from above (1.46 g) in CH₂Cl₂ at room temperature was added Dess-Martin reagent (5.6 g) portionwise and one drop of water and let stir over the weekend at room temperature 10% Na₂S₂O₃ was added and stirred for 20 min, extracted with CH₂Cl₂, washed with saturated sodium bicarbonate, dried with Na₂SO₄, and concentrated in vacuo to afford 1.1 g of product (76%).

Preparative Example 34.13

The above compound was prepared according to the procedure set forth in EP 0 555 153 A1 (the disclosure of which is incorporated herein by reference thereto).

Preparative Example 34.14

The aldehyde (500 mg) from above was reacted following the procedure set forth in the Preparative Example 13.4, Step A to yield 372 mg of product (76%).

Preparative Example 34.15-34.16

Following the procedures set forth in Preparative Example 34.8 but using the nitroalkanes indicated in the table below, the aldehydes were prepared,

PREP. YIELD Ex. NITROALKANE ALDEHYDE (%) 34.15

17 34.16

21

Preparative Example 34.17

To a stirred suspension of 5-bromo-2-furoic acid (15.0 g, 78.54 mmol) in 225 mL of CH₂Cl₂ at room temperature was added oxalyl chloride followed by a catalytic amount of N,N′-dimethylforamide. After 1 h, ethanol (20 mL) was added followed by triethylamine (22 mL). Reaction was continued for 15 h. The mixture was concentrated under reduced pressure to a residue, which was extracted with excess volume of hexanes, and hexanes-CH₂Cl₂ (3:1, v/v). The extracts were filtered, the filtrated was concentrated to a yellow oil, dried on high vacuum, yielding 17.2 g (93%) of the desired ester.

Step B

The ester product obtained from Step A above (17.2 g, 73.18 mmol) was converted to 2-ethyl-4-tertbutyl-5-bromo-furoate (7.9 g, 37%) using the literature procedure. J. Am. Chem. Soc., 1939, 61, 473-478 (the disclosure of which is incorporated herein by reference thereto).

Step C

The ester product obtained from Step B above (7.9 g, 27.13 mot) was reduced to the alcohol (6.32 g) using the procedure set forth in Preparative Example 34.8, Step C.

Step D

The product obtained from Step C above (6.32 g) was dissolved in 140 mL of THF and cooled in a −78° C. bath. A 2.5 M solution of n-butyllithium in hexanes (22 mL, 55.0 mmol) was added dropwise along the side wall of the flask. After 15 min, H₂O (˜70 mL) was added. Cooling bath was removed, the mixture was stirred for an additional 1 h. Brine (50 mL) and CH₂Cl₂ (300 mL) were added, the two layers were separated, the aqueous layer was extracted with CH₂Cl₂ (100 mL), and the combined organic layers were dried by Na₂SO₄. Evaporation of solvents afforded 5.33 g (crude) of the debrominated product as a reddish brown oil.

Step E

The alcohol product obtained from Step D above (5.33 g) was oxidized to the corresponding aldehyde (3.06 g, 74% over three steps) using the procedure set forth in Preparative Example 34.8, Step D.

Preparative Example 34.18

Step A

To a stirred solution of cyclopropyl bromide (4.0 mL, 50 mmol) in 120 mL of ether at −78° C. was added dropwise a 1.7M solution of t-butyllithium in pentane (44.5 mL, 75.7 mmol). After 10 min, cooling bath was removed, stirring was continued for 1.5 h. The mixture was cooled again in a −78° C. bath, and 3-furaldehyde (3.5 mL, 41.9 mmol) was added. Reaction was continued for 1 h, and quenched with a saturated NH4Cl aqueous solution. The aqueous mixture was extracted with CH₂Cl₂ (100 mL×3). The organic extracts were washed with brine, dried by Na₂SO₄, filtered, and concentrated in vacuo to give 5.3 g (91%) of the alcohol product as a yellow oil.

Step B

Chloro trimethylsilane (27.2 mL, 214.2 mmol) was added dropwise to a vigorously stirred suspension of sodium iodide (32 g, 213.5 mmol) in 100 mL of acetonitrile. After 5 min, a solution of the alcohol obtained from Step A above (4.93 g, 35.68 mmol) in 100 mL of acetonitrile was added dropwise. Stirring was continued for 5 min. H₂O (100 mL) was added, the layers were separated, and the aqueous layer was extracted with ether (100 mL×2). The organic layers were combined, washed with a 10% Na₂S₂O₃ aqueous solution and brine, and dried over Na₂SO₄. Evaporation of solvents gave a dark brown oil, which was filtered through a 5-in silica get column, eluting with CH₂Cl₂-hexanes (1:3.5, v/v), Removal of solvents afforded 4.22 g (47%) of the iodo product as a light yellow oil.

Step C

The iodo-product obtained from Step B above (2.2 g, 8.8 mmol) was dissolved in 60 mL of ether, and stirred in a −78° C. bath. A 1.7 M solution of t-butyllithium in pentane (10.4 mL, 17.7 mmol) was added dropwise. After 20 min, cooling bath was removed. Reaction was continued for 2.5 hr and quenched with H₂O (20 mL). The aqueous mixture was stirred overnight and separated. The aqueous layer was extracted with ether (30 mL). The combined organic layers were washed with brine, dried by Na₂SO₄, and filtered through a Celite pad. Removal of solvent gave 1.10 g (100%) of 3-butylfuran as a reddish-yellow oil.

Step D

3-Butylfuran (1.1 g, 8.8 mmol), obtained from Step C above, was dissolved in 60 mL of ether, and stirred in a −78° C. bath. A 1.7 M solution of t-butyllithium in pentane (6.0 mL, 10.2 mmol) was added dropwise along the side wall of the flask. The mixture was stirred for 3 h from −78° C. to 0° C., and continued for 1 h at room temperature. A solution of N,N′-dimethylforamide (1.1 mL, 14.23 mmol) was added. Reaction was continued overnight, and quenched with a saturated NH₄Cl aqueous solution. The two layers were separated, the aqueous layer was extracted with CH₂Cl₂ (30 mL×2). The combined organic layers were washed with brine, dried with Na₂SO₄, and concentrated to an oil, which was purified by preparative TLC (CH₂Cl₂-hexanes=1:1.5, v/v) to give 0.48 g (36%) of the aldehyde (contaminated by some 3-butyl-2-furaldehyde).

Preparative Example 34.19

Step A

3-Ethylfuran was prepared from 3-hydroxymethylfuran according to literature procedure: J. Org. Chem., 1983, 48, 1106-1107 (the disclosure of which is incorporated herein by reference thereto).

Step B

3-Ethylfuran obtained from Step A above was converted to 4-ethyl-2-furaldehyde using the procedure set forth in Preparative Example 34.32, Step D.

Preparative Examples 35-51.21

Following the procedure set forth in Preparative Example 34 but using the commercially available aldehydes and Grignard reagents listed in the Table below, the amine products below were obtained.

Prep Grignard 1. Yield Ex. Aldehyde Reagent Amine 2. MH⁺ 35

EtMgBr

1. 65% 2. 154 36

EtMgBr

1. 75% 2. 180 37

EtMgBr

1. 78% 2. 170 38

EtMgBr

1. 34% 2. 204 39

EtMgBr

1. 68% 2. 150 40

EtMgBr

1. 40% 2. 220 41

EtMgBr

1. 73% 2. 154 42

EtMgBr

1. 52% 2. 220 43

EtMgBr

1. 55% 2. 180 44

EtMgBr

1. 20% 2. 204 45

EtMgBr

1. 80% 2. 166 46

EtMgBr

1. 35% 2. 220 47

i-PrMgBr

1. 20% 2. 150 48

EtMgBr

1. 77% 2. [M-NH₂]⁺ = 149 49

EtMgBr

1. 77% 2. 172 50

EtMgBr

1. 78% 2. [M-NH₂]⁺ = 147 51

EtLi

1. 10% 2. 116 51.2

EtMgBr

1. 37% 2. 161 51.3

EtMgBr

1. 63% 2. 216 51.4

EtMgBr

1. 71% 2. 228 51.5

EtMgBr

1. 89% 2. 168 51.6

EtMgBr

1. 20% 2. 228 51.8

EtMgBr

1. 36% 2. 222 51.10

1. 95% 2. 152.1 51.11

EtMgBr

61% 2. 138.1 MH⁺-H₂O 51.12

EtMgBr

1. 70% 2. 184.1 51.18

EtMgBr

1. 42% 2. 147 [M-NH₂]⁺ 51.19

EtMgBr

1. 67% 2. 204 51.20

EtMgBr

1. 33% 2. 188 51.21

t-BuLi

1. 7% 51.22

t-BuLi

1. 20% 2. 205 (M-NH₂)⁺

Preparative Examples 51.25-51.31

Following the procedure set forth in Example 34 but using the commercially available aldehydes and Grignard reagents listed in the Table below, the amine products were obtained.

Grignard Yield Prep Ex. Aldehyde Reagent Amine (%) 51.25

EtMgBr

20 51.26

77 51.27

EtMgBr

51 51.28

56 51.29

54 51.30

EtMgBr

80 51.31

—≡—MgBr

10

Preparative Example 52

Step A

A mixture of 2-(trifluoroacetyl)thiophene (2 mL, 15.6 mmol), hydroxylamine hydrochloride (2.2 g, 2 eq), diisopropylethylamine (5.5 mL, 2 eq) and MeOH (50 mL) was stirred at reflux for 48-72 hrs, then concentrated in vacuo. The residue was diluted with EtOAc, washed with 10% KH₂PO₄ and dried over Na₂SO₄ (anhydrous). Filtration and concentration afforded the desired oxime (2.9 g, 96%) which was used directly in Step B without further purification.

Step B

To a mixture of the product from Step A above in TFA (20 mL) was added Zn powder (3 g, 3 eq) portionwise over 30 min and stirred at room temperature overnight. The solid was filtered and the mixture reduced in vacuo. Aqueous NaOH (2) was added and the mixture was extracted several times with CH₂Cl₂. The organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated to afford the desired product (1.4 g, 50%).

Preparative Examples 53-61

Following the procedure set forth in Preparative Example 52 but using the commercially available ketones listed in the Table below, the following amines were obtained.

Prep Ex- 1. Yield (%) ample Ketone Amine 2. MH⁺ 53

1. 11 2. 128 54

1. 33 2. 142 55

1. 49 2. 156 56

1. 5 2. 154 57

1. 47 2. 174 58

1. 71 2. 190 59

1. 78 2. 191 60

1. 80 2. 190 61

1. 9 2. 156

Preparative Example 62

To a cooled (0-5° C.) suspension of L-α-(2-thienyl)glycine (0.5 g) and LiBH₄ (2M in THF, 3.8 mL) in anhydrous THF (10 mL) was slowly added a THF (5 mL) solution of iodine (0.8 g). After stirring at room temperature for 15 min, the mixture was stirred at relux overnight. After cooling to room temperature, MeOH was added dropwise until gas evolution ceased and after 30 min, the mixture was evaporated. The oily residue was stirred in 20 mL KOH for 4 hrs, diluted with brine and extracted with EtOAc.

The organic phase was dried over anhydrous MgSO₄, filtered and concentrated in vacuo to afford a crude mixture. Purification by flash column chromatography (50% EtOAc/CH₂Cl₂, silica) afforded the product (0.3 g, 63%, MH⁺=144).

Preparative Example 63

CeCl₃-7H₂O was dried at 140-150° C. for 22 hr. To this solid was added THF (80 mL, anhydrous) and after stirring for 2 hr, the suspension was cooled to −78° C. and to it was added methyl lithium over 30 min. After stirring for an additional 30 min 2-thiophenecarbonitrile dissolved in anhydrous THF (4.5 mL) was added and the resulting mixture stirred for an additional 4.5 hr at 78° C. Concentrated aqueous NH₃ (25 mL) was added and the mixture was warmed to room temperature and filtered through celite. The filtrate was extracted with dichloromethane, dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to afford a crude mixture. Purification by flash column chromatography (5% MeOH, CH₂CO₂, silica) afforded the desired product (1.2 g 62%).

Preparative Example 64

Step A

To a solution of (D)-valinol (4.16 g, 40.3 mmol) in CH₂Cl₂ (60 mL) at 0° C. was added MgSO₄ (20 g) followed by dropwise addition of 3-fluorobenzaldehyde (5.0 g, 40.3 mmol). The heterogenous solution was stirred at 0° C. for 2 h and was allowed to warm to room temperature and stir overnight (14 h). The mixture was filtered and the drying agent was washed with CH₂Cl₂ (2×10 mL). The filtrate was concentrated under reduced pressure to afford 8.4 g (100%) of an oil which was taken onto the next step without further purification.

Step B

To a solution of the imine (8.4 g, 40.2 mmol) from Step A in CH₂Cl₂ (60 mL) at room temperature was added Et₃N (6.2 mL, 44.5 mmol) followed by dropwise addition of TMSCl (5.7 mL, 44.5 mmol). The mixture was stirred for 6 h at room temperature whereupon the ppt that had formed was filtered off and washed with CH₂Cl₂ (2×10 mL). The combined filtrate was concentrated under reduced pressure and was taken up in Et₂O/hexane (1:1/150 mL). The precipitate was filtered off and the filtrate was concentrated under reduced pressure to afford 10.1 g (89%) of the protected imine as an oil. This material was taken onto the next step without further purification.

Step C

To a solution of EtI (4.0 g, 25.6 mmol) in Et₂O (40 mL) at −78° C. was added t-BuLi (30.1 mL, 51.2 mmol, 1.7 M in pentane) and the mixture was stirred for 10 min. The mixture was warmed to room temperature, stirred for 1 h, and was recooled to −40° C. A solution of the imine (6.0 g, 21.4 mmol) from Step B in Et₂O (30 mL) was added dropwise via addition funnel to afford a bright orange mixture. The reaction mixture was stirred for 1.5 h at −40° C. then 3M HCl (50 mL) was added and the mixture was allowed to warm to room temperature. Water (50 mL) was added and the layers were separated. The aqueous layer was extracted with Et₂O (2×30 mL) and the organic layers were combined and discarded. The aqueous layer was cooled to 0° C. and carefully treated with solid NaOH pellets until pH=12 was attained. The aqueous layer was extracted with Et₂O (3×30 mL) and the combined layers were washed with brine (1×30 mL). The organic layer was dried (Na₂SO₄), filtered, and concentrated under reduced pressure to afford 4.8 g (94% yield) of the amine as an is oil. This material was taken on crude to the next step without further purification.

Step D

To a solution of amine (4.5 g, 18.8 mmol) from Step C in MeOH (80 mL) at room temperature was added MeNH₂ (25 mL, 40% in water) followed by addition of a solution of H₅IO₆ (14.0 g, 61.4 mmol) in H₂O (25 mL). The heterogenous mixture was stirred for 1.5 h (until the reaction was complete by TLC) and the precipitate was filtered off. The resulting filtrate was diluted with water (50 mL) and the mixture was extracted with Et₂O (4×60 mL). The combined organic layers were concentrated to a volume of ˜30 mL whereupon 3M HCl (75 mL) was added. The mixture was stirred overnight (12 h at room temperature) after which the mixture was concentrated to remove the volatiles. The aqueous layer was extracted with Et₂O (3×40 mL) and the organic layers were discarded. The aqueous layer was cooled to 0° C. and was carefully treated with solid NaOH pellets until pH ˜12 was reached. The aqueous layer was extracted with Et₂O (3×60 mL) and the combined organic layers were dried (MgSO₄). The organic layer was concentrated under reduced pressure to afford 2.8 g (97% yield) of the desired amine as an oil [MH⁺ 154]. This compound was proven to be >85% pure by ¹H NMR and was used crude in the subsequent coupling step.

Preparative Examples 65-75.10J

Following the procedure set forth in Preparative Example 64 but using the prepared or commercially available aldehydes, amino alcohols, and organolithium reagents in the Table below, the optically pure amine products in the Table below were obtained.

Prep Amino Organo 1. Yield (%) Ex. Aldehyde Alcohol lithium Product 2. MH⁺ 65

EtLi

1. 62 2. 154 66

EtLi

1. 70 2. 154 67

1. 54 2. 166 68

1. 67 2. 166 69

EtLi

1. 67 2. 154 70

EtLi

1. 42 2. 142 71

EtLi

1. 36 2. 142 72

1. 62 2. 148 73

t-BuLi

1. 27 2. 256 74

t-BuLi

1. 15 2. 164 75

1. 7 2. 204 75.1

EtLi

1. 65 2. 123 [M − NH₂]⁺ 75.2

EtLi

1. 62 2. 123 [M − NH₂]⁺ 75.3

EtLi

1. 93 2. 139 [M − NH₂]⁺ 75.4

t-BuLi

1. 50 2. 167 [M − NH₂]⁺ 75.5 (34.6)

t-BuLi

1. 48 2. 167 [M − NH₂]⁺ 75.6 (34.6)

EtLi

1. 97 2. 139 [M − NH₂]⁺ 75.7 (34.6)

iPrLi

1. 87 2. 153 [M − NH₂]⁺ 75.8 (34.6)

1. 94 2. 151 [M − NH₂]⁺ 75.9 (34.8)

EtLi

1. 75 2. 151 [M − NH₂]⁺ 75.10 (34.8)

tBuLi

1. 30 2. 179 [M − NH₂]⁺ 75.10A (34.7)

1. 61 2. 135 [M − NH₂]⁺ 75.10B (34.19)

EtLi

1. 24 2. 154 75.10C (34.18)

EtLi

1. 32 2. 165 [M − NH₂]⁺ 75.10D (34.8)

MeLi

1. 47 2. 137 [M − NH₂]⁺ 75.10E (34.8)

iPrLi

1. 30 2. 165 [M − NH₂]⁺ 75.10F (34.8)

1. 67 2. 163.0 [M − NH₂]⁺ 75.10G (34.17)

EtLi

1. 24 2. 165 [M − NH₂]⁺ 75.10H (34.15)

EtLi

1. 70 2. 194 75.10J (34.16)

EtLi

1. 54 2. 208

Preparative Examples 75.11-75.59

Following the procedure set forth in Preparative Example 64 but using the prepared or commercially available aldehydes, amino alcohols, and organolithium reagents in the Table below and carrying the amine on crude, the optically pure amine products in the Table below were obtained.

Prep Amino Organo Yield Ex. Aldehyde Alcohol lithium Product (%) 75.11

52 75.12

50 75.13

iPrLi

57 75.14

iPrLi

54 75.15

iPrLi

58 75.16

61 75.17

EtLi

72 75.18

68 75.19

iPrLi

77 75.20

t-BuLi

15 75.21

MeLi

50 75.22

EtLi

23 75.24

EtLi

20 75.27

EtLi

65 75.28

iPrLi

61 75.29

EtLi

90 75.30

iPrLi

62 75.31

iPrLi

43 75.32

50 75.33

50 75.34

tBuLi

51 75.35

MeLi

51 75.36

tBuLi

57 75.37

tBuLi

60 75.38

EtLi

73 75.39

MeLi

48 75.41

52 75.42

EtLi

40 75.43

tBuLi

20 75.44

t-BuLi

79 75.45

iPrLi

55 75.46 (75.57)

tBuLi

39 75.47 (75.57)

iPrLi

55 75.48 (75.57)

34 75.49 (34.7)

EtLi

61 75.50 (34.7)

tBuLi

25 75.51 (34.2)

iPrLi

33 75.52 (34.2)

tBuLi

30 75.53 (34.2)

EtLi

39 75.54 (34.2)

38 75.55

EtLi

64 75.56

EtLi

46 75.57 (75.57)

EtLi

62 75.58

iPrLi

24 75.59 (34.1)

EtLi

70 75.60

t-BuLi

60 75.61

iPrLi

60 75.62

t-BuLi

57 75.63

EtLi

94 75.64

t-BuLi

46 75.65

t-BuLi

60 75.66

t-BuLi

15 75.67

t-BuLi

60 75.68

MeLi

60 75.69

t-BuLi

12

Preparative Example 75.75

Step A

To a solution of aldehyde (2.5 g) in ether (50 ml) at 0° G was added EtMgBr (4.56 ml) dropwise. The heterogenous mixture was stirred for 2 hr at 0° C. and then poured into a beaker of saturated ammonium chloride (25 ml), ice and CH₂Cl₂ (30 ml). After the biphasic mixture stirred for 10 min, the organic layer was separated, washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo to afford the product (2.41 g, 95%)

Step B

To a solution of alcohol from Step A above (1 g) in toluene at room temperature was added DPPA. The mixture was cooled to 0° C. and DBU was added and let stir for 12 hr at room temperature. The layers were separated and the organic layer was washed with water, 1N HCl and dried over Na₂SO₄, filtered, and concentrated in vacuo. Purified by preparative plate chromatography (hexane/EtOAc 20/1) to give the product (840 mg, 75%).

Step C

To a solution of azide (730 mg) from Step B above in THF (7 ml) was added PPh₃ (1 g). The heterogenous solution was stirred for 12 hr, whereupon water (1.5 ml) was added. The mixture was refluxed overnight, cooled to room temperature and concentrated in vacuo. Ether and 1N HCl were added to the residue. The aqueous layer was cooled to 0° C., basified with NaOH pellets and extracted with ether. The ether layer was dried over MgSO₄, filtered, and concentrated in vacuo to afford the product (405 mg, 62%).

Step D

To a solution of azide in THF at −10° C. was added LiAiH₄ portionwise. The heterogenous solution was stirred at room temperature for 1 hr and then refluxed for 4 hr. The solution was cooled to 0° C. and water, 2M NaOH and ether were added to the reaction. The mixture was filtered through a celite pad. The filtrate was treated with 3N HCl. The aqueous layer was cooled to 0° C., basified with NaOH pellots and extracted with ether. The ether layer was dried over MgSO₄, filtered, and concentrated in vacuo to afford the product.

Preparative Example 75.76-75.90

Following a similar procedure set forth in Preparative Example 75.75, and using the reduction procedure indicated, the following amines were obtained.

Prep Reducing % Ex. Aldehyde Step Product Yield 75.76

D

43 75.77

C

36 75.78

D

32 75.79

C

42 75.80

D

56 75.81

D

35 75.82

C

13 75.83

C

42 75.84

C

39 75.85

C

26 75.86

C

25 75.87

C

14 75.88 (34.14)

C

49 75.89 (34.13)

C

34 75.90

C

44 75.92

C

74 75.93

C

81

Preparative Example 75.200

If one were to follow a similar procedure as that in Preparative Example 64, but using the aldehyde from Preparative Example 1004A and cyclopentyllithium instead of ethyllithium, the title aldehyde could be prepared.

Preparative Example 75.201

If one were to follow a similar procedure as in Preparative Example 75.200, but using 5-methylfuranaldehyde instead of the aldehyde from Preparative Example 1004A the title aldehyde could be prepared.

Preparative Example 76

The desired compound was prepared according to methods previously described in J. Med. Chem. 1996, 39, 3319-3323 (the disclosure of which is incorporated herein by reference thereto).

Preparative Example 76.1

Step A

To a solution of amine from Preparative Example 75.90 (2.22 g) in CH₂Cl₂ (50 ml) at 0° C. was added TEA (3.03 ml) followed by BOC₂O (2.85 g). The heterogenous mixture was allowed to stir at room temperature overnight. 10% Citric acid was added to the reaction and the layers were separated. The organic layer was washed with saturated sodium bicarbonate, brine and dried with Na₂SO₄, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography (Hex/EtOAc 10:1) to afford 2.7 g of an oil (81%).

Step B

Following the procedure from Preparative Example 13.4, Step A, but using the product from Step A above (450 mg) and 3-thiophene boronic acid (284 mg), the product was prepared (325 mg, 71%).

Step C

To the product from Step B (325 g) was added 4M HCl in dioxane (1.31 ml) and let stir for 1 hr. The reaction was concentrated in vacuo and taken up in CH₂Cl₂ and concentrated in vacuo again. This procedure was repeated 5 times to afford a semisolid (89%).

Preparative Example 76.2-76.3

Following the procedures set forth in Preparative Example 76.1; but using the commercially available boronic acids, the indicated amines were prepared.

Prep Boronic Yield Ex. Acid Product (%) 76.2

70 76.3

35

Preparative Example 76.10

Step A

The product from Preparative Example 75.75, Step A (2.5 g) was reacted via the Preparative Example 13.11, Step B to give the ketone (1.93 g, 78%).

Step B

To a solution of ketone from Step A above (500 mg) in THF (5 ml) at 0° C. was added S-2-methyl-CBS-oxazaborolidine (0.98 ml) dropwise followed by BH₃Me₂S (1.48 ml). The mixture was stirred at 0° C. for 2 hr and was allowed to warm to room temperature and stir overnight. The mixture was cooled to 0° C. and treated with MeOH (10 ml). After stirring for 20 min, the reaction was concentrated in vacuo. The residue was dissolved in CH₂Cl₂ and washed with 1M HCl, saturated sodium bicarbonate water and brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude material was purified by preparative plate chromatography (Hex/EtOAc 4:1) to afford 650 mg of an oil (89%).

Step C

The chiral alcohol from Step B above was reacted via the Preparative Example 75.75 Step B to give the azide.

Step D

The azide from Step C above was reacted via the Preparative Example 75.75 Step C to give the amine product.

Preparative Example 76.11

The desired compound was prepared as in Preparative Example 76.10, but using the R-2-methyloxazaborolidine in step B.

Preparative Example 77

The desired compound was prepared according to methods previously described in J. Med. Chem. 1996, 39, 3319-3323 (the disclosure of which is incorporated herein by reference thereto).

Preparative Example 78

The desired compound was prepared according to methods previously described in Chem. Pharm. Bull. 1991, 39, 181-183 (the disclosure of which is incorporated herein by reference thereto),

Preparative Example 78.1

The desired compound was prepared according to methods previously described in J. Organometallic Chem. 1998, 567, 31-37 (the disclosure of which is incorporated herein by reference thereto).

Preparative Example 79

The desired compound was prepared according to methods previously described in Chem. Pharm. Bull. 1991, 39 181-183 (the disclosure of which is incorporated herein by reference thereto).

Preparative Example 80

The desired compound was prepared according to methods previously described in (a) Synthesis 1987, 998-1001, (b) Synthesis 1996, 641-646, and (c) J. Med. Chem. 1991, 34, 2176-2186 (the disclosures of each reference being incorporated herein by reference thereto).

Preparative Example 81

The desired compound was prepared according to methods previously described in (a) Synthesis 1987, 998-1001, (b) Synthesis 1996, 641-646 and (c) J. Med. Chem. 1991, 34, 2176-2186 (the disclosures of each reference being incorporated herein by reference thereto).

Preparative Example 82

The desired compound was prepared according to methods previously described in J. Med. Chem. 1988, 31, 2176-2186 (the disclosure of which is incorporated herein by reference thereto).

Preparative Example 83

To a solution of carboxylic acid (1.5 g, 7.89 mmol) in H₂O/acetone (1.10/12 mL total) at 0° C. was added Et₃N (1.43 mL, 10.3 mmol) followed by addition of ethyl chloroformate (0.83 mL) 8.68 mmol). The resulting mixture was stirred for 30 min after which a solution of NaN₃ (0.7 g, 11.8 mmol) in H₂O (2 mL) was added dropwise. The resultant heterogenous mixture was stirred for 1 h at 0° C., then cold water (5 mL) and Et₂O (10 mL) were added. The layers were separated and the aqueous layer was extracted with Et₂O (2×10 mL). The organic layers were combined, toluene (20 mL) was added, and the organic layers were dried (MgSO₄) and concentrated under reduced pressure to a volume of 20 mL. t-BuOH (5 mL) was added and the mixture was refluxed for 12 h. The mixture was concentrated under reduced pressure and the crude residue was taken up in 3M HCl (30 mL) and was heated at reflux for 12 h. The mixture was cooled to room temperature and extracted with Et₂O (3×15 mL). The aqueous layer was cooled to 0° C. and solid NaOH pellets were added until pH ˜12 was reached. The aqueous layer was extracted with Et₂O (3×30 mL) and the combined organic layers were dried (MgSO₄) and concentrated under reduced pressure to afford 0.78 g (61% yield) of an oil [MH⁺ 162]. This material was used without further purification.

Preparative Example 84

The corresponding cyclopropyl analog was prepared according to the procedure outlined in Preparative Example 83.

Preparative Example 85

The corresponding cyclohexyl analog was prepared according to the procedure outlined in Preparative Example 83.

Preparative Example 86

The desired compound was prepared according to methods previously described in J. Org. Chem. 1978, 43, 892-898 (the disclosure of which is incorporated is herein by reference thereto).

Preparative Example 88.2

Step A

2-Methylthiophene (3 g) was dissolved in THF and cooled to 40° C. N-butyllithium (2.5M in hexane, 12.24 ml) added dropwise and let stir at −40° C. for 30 min. CuBr.(CH₃)₂S (6.29 g) added and let warm to −25° C. where the trifluoroaceticanhydride (4.32 ml) was added. The reaction was stirred at −15° C. over the weekend. The reaction was quenched with saturated ammonium chloride and extracted with EtOAc. The organic layer washed with brine, dried with MgSO₄, filtered and concentrated in vacuo to give 4.59 g of an oil (78%).

Step B

The product from Step A (4.58 g), hydroxylamine hydrochloride (3 g), sodium acetate (4.4 g), EtOH (75 ml) and 1420 (7.5 ml) were combined and heated to 75° C. overnight. The reaction was concentrated in vacuo, taken up 1N HCl extracted with ether, dried with MgSO₄, filtered and concentrated in vacuo to give 4.58 g of the product (93%, MH+=210).

Step C

The product from Step B above (4.5 g) was dissolved in TFA (40 ml) and cooled to 0° C. Zn powder (4.2 g) was added portionwise and let reaction warm to room temperature and stir overnight. The reaction was concentrated in vacuo, taken up in 1N NaOH, extracted with ether, dried with MgSO₄, filtered and concentrated in vacuo to give 3.43 g of the product (80%).

Preparative Example 89

To a solution of KH (0.45 g, 11.3 mmol) in THF (15 mL) at room temperature was added amine hydrochloride (0.85 g, 5.1 mmol) portionwise to afford a heterogenous reaction mixture. The mixture was allowed to stand overnight (12 h) and MeI (0.32 mL, 5.1 mmol) was added dropwise. The mixture was stirred for 6 h after which the mixture was carefully poured into cold brine (125 mL). The mixture was extracted with Et₂O (3×25 mL) and the organic layers were combined. The organic layer was dried (Na₂SO₄), filtered, and concentrated under reduced pressure to afford the crude product as an oil. This material was carried on crude to the coupling step without further purification or characterization.

Preparative Example 89.1

To a solution of KH (1.1 g) in THF (20 ml) at room temperature was added (R)-2-amino-1-butanol 48 ml) dropwise to afford a heterogenous mixture. The mixture was allowed to stand overnight (18 hr) and then MeI (1.59 ml) was added dropwise. The mixture was stirred for 4 hr after which brine was added. Extracted with ether, dried with K₂CO₃, filtered and concentrated in vacuo to afford 1.75 g of an oil.

Preparative Example 89.2

To a solution of KH (1.1 g) in THF (20 ml) at room temperature was added (S)-2-amino-1-butanol 48 ml) dropwise to afford a heterogenous mixture. The mixture was allowed to stand overnight (18 hr) and then MeI (1.59 ml) was added dropwise. The mixture was stirred for 4 hr after which brine was added. Extracted with ethers dried with K₂CO₃, filtered and concentrated in vacuo to afford 1.75 g of an oil.

Preparative Example 90

The corresponding cis analog was prepared in an analogous fashion utilizing the procedure described in Preparative Example 89. This material was also used without further purification.

Preparative Example 91

The desired compound was prepared according to methods previously described in J. Org. Chem. 1987, 52 4437-4444 (the disclosure of which is incorporated herein by reference thereto).

Preparative Example 92

The desired compound was prepared according to methods previously described in Bull. Chem. Soc. Jpn. 1962, 35, 11-16 (the disclosure of which is incorporated herein by reference thereto).

Preparative Example 93

The desired amine was prepared from the corresponding ketone according to standard methods previously described in (a) Synthesis 1987, 998-1001, (b) Synthesis 1996, 641-646 and (c) J. Med. Chem. 1991, 34, 2176-2186 (the disclosures of each being incorporated herein by reference thereto).

Preparative Example 94

The desired amine was prepared from the corresponding ketone according to standard methods previously described in (a) Synthesis 1987, 998-1001, (b) Synthesis 1996, 641-64 and (c) J. Med. Chem. 1991, 34, 2176-2186 (the disclosures of each being incorporated herein by reference thereto).

Preparative Example 95

Step A

Lithium hexamethyldisilylazide (34 mL, 1M in THF) was added dropwise to a −78° C. THF (20 mL) solution of isobutyronitrile (2.8 mL). After 40 min, cyclopropyl-methylbromide (5 g) was added and the mixture warmed to and stirred at 25° C. overnight. After cooling to 0° C., 1M HCl (aq) was added and the mixture was extracted with diethyl ether, dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo at 0° C. to give the desired product (4.5 g).

Step B

Methyl Lithium (17 mL, 14 M in Et₂O) was added to the product from Step A above (1.5 g) in Et₂O (anhydrous) at 0° C. The mixture was stirred at 0-25° C. overnight, then diluted with 3M HCl (aq), extracted with CH₂Cl₂, dried over anhydrous Na₂SO₄, filtered, concentrated in vacuo at 0° C. and used directly in Step C.

Step C

The product from Step B above was added to a slurry of NaBH₄ (1.4 g) in isopropanol (50 mL) at 0° C., then the mixture was stirred at reflux for 8 hr and at room temperature for 48 hrs. Water was added and the mixture was stirred for 30 min, then extracted with diethyl ether, dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was diluted with CH₂Cl₂ and extracted with 3M HCl. The organic phase was discarded and the aqueous phase was basified with NaOH (aq) and extracted with CH₂Cl₂. Drying over anhydrous Na₂SO₄, filtering, and concentration in vacuo gave the desired compound (0.5 g).

Preparative Example 96

Step A

2-Thiopohenecarbonyl chloride (2.0 mL, 18.7 mmol) was dissolved in 100 mL dichloromethane. After addition of diisopropylethylamine (4.1 mL, 23.4 mmol) and Boc-piperazine (3.66 g, 19.7 mmol), the mixture was stirred for 4 h at room temperature. The resulting mixture was put into water (500 mL) and acidified with 3N HCl to pH ˜1. Extraction with dichloromethane (2×100 mL) and drying over sodium sulfate resulted in sufficiently pure product that was used in the next step without any further purification. ¹H NMR (300 MHz, d₆-DMSO) 1.60 (s, 9H), 3.29 (dd, 4H), 3.69 (dd, 4H), 7.23 (dd, 1H), 7.49 (d, 1H), 7.79 (d, 1H).

Step B

The crude material from Step A was dissolved in trifluoroacetic acid/dichloromethane (75 mL, 4/1). After stirring for 2 h, the reaction mixture was put into 1N sodium hydroxide (400 mL). Extraction with dichloromethane (2×100 mL) and drying over sodium sulfate resulted in sufficiently pure product that was used in Step C without any further purification. ¹H NMR (300 MHz, d₆-DMSO) 2.81 (dd, 4H), 3.63 (dd, 4H), 7.21 (dd, 1H), 7.46 (d, 1H), 7.82 (d, 1H).

Step C

The crude material (3.50 g, 17.8 mmol) from Step B was dissolved in dichloromethane (100 mL). After addition of diisopropylethylamine (18.7 mL, 107 mmol), 3-nitrosalicylic acid (3.3 g, 18.0 mmol), and PyBrOP (10.4 g, 22.3 mmol), the resulting mixture was stirred over night at room temperature before being put into 1N sodium hydroxide (200 mL). Extraction with dichloromethane (2×200 mL) removed all PyBrOP by-products. The aqueous phase was acidified with 3N HCl and subsequently extracted with dichloromethane (3×100 mL). The combined organic phases of the acidic extraction were dried over sodium sulfate, concentrated, and finally purified by column chromatography (dichloromethane/methanol 10/1) to yield the desired product (2.31 g, 34% over 3 steps). ¹H NMR (300 MHz, d₆-DMSO) 3.30-3.90 (m, 8H), 7.10-8.20 (m, double signals due to E/Z-isomers, 6H), 10.82 (s, 1H).

Step D

The nitro-compound (2.3 g, 6.4 mmol) from Step C was dissolved in methanol (50 mL) and stirred with 10% Pd/C under a hydrogen gas atmosphere over night. The reaction mixture was filtered through Celite and washed thoroughly with methanol. Finally, the filtrate was concentrated in vacuo and purified by column chromatography (dichloromethane/methanol=10/1) to yield the desired product (1.78 g, 84%). ¹H NMR (300 MHz, d₆-DMSO) 3.30-3.90 (m, 8H), 7.22 (m, 2H), 7.55 (d, 1H), 7.71 (d, 1H), 7.88 (d, 1H), 8.15 (d, 1H), 10.85 (bs, 1H).

Preparative Example 97

Step A

Picolinic acid (3.0 g, 24.3 mmol) was suspended in SOCl₂ (15 mL). After addition of dimethylformamide (5 drops), the reaction mixture was stirred for 4 hours. Evaporation of the solvent yielded the corresponding acid chloride as HCl-salt. Without any further purification, the solid was suspended in 120 mL dichloromethane. After addition of diisopropylethylamine (12.7 mL, 73 mmol) and Boc-piperazine (4.8 g, 25.5 mmol), the reaction was stirred over night at room temperature. The resulting mixture was put into water (500 mL) and extracted with dichloromethane (2×100 mL). Drying over sodium sulfate resulted in sufficiently pure product that was used in Step B without any further purification. ¹H NMR (300 MHz, d₆-DMSO) 1.63 (s, 9H), 3.21 (dd, 4H), 3.61 (dd, 4H), 7.57 (dd, 1H), 7.63 (d, 1H), 7.98 (dd, 1H), 8.70 (d, 1H).

Step B

The crude material from Step A was dissolved in trifluoroacetic acid/dichloromethane (75 mL, 4/1). After stirring for 2 days, the reaction mixture was put into 1N sodium hydroxide (400 mL). Extraction with dichloromethane (2×100 mL) and drying over sodium sulfate resulted in sufficiently pure product that was used in Step C without any further purification. ¹H NMR (300 MHz, d₆-DMSO) 2.77 (dd, 2H), 2.83 (dd, 1H), 3.38 (dd, 2H), 3.64 (dd, 1H), 7.58 (dd, 1H), 7.62 (d, 1H), 8.00 (dd, 1H), 8.67 (d, 1H).

Step C

The crude material (1.35 g, 7.06 mmol) from Step B was dissolved in dichloromethane (50 mL). After addition of diisopropylethylamine (3.7 mL, 21.2 mmol), 3-nitrosalicylic acid (1.36 g, 7.41 mmol), and PyBrOP (3.62 g, 7.77 mmol), the resulting mixture was stirred over night at room temperature before being put into 1N sodium hydroxide (300 mL). Extraction with dichloromethane (2×100 mL) removed any PyBrOP products. The aqueous phase was acidified with 3N HCl. Adjustment of the pH with saturated sodium carbonate solution to almost neutral crushed the desired compound out of solution. The aqueous phase was subsequently extracted with dichloromethane (3×100 mL). The combined organic layers of the neutral extraction were dried over sodium sulfate, concentrated, and finally purified by column chromatography (dichloromethane/methanol=20/1) to yield the desired product (1.35 g, 16% over 3 steps). ¹H NMR (300 MHz, d₆-DMSO) 3.30-3.95 (m, 8H), 7.22 (m, 1H), 7.61 (m, 1 h), 7.73 (d, 2H), 8.03 (m, 1H), 8.17 (m, 1H), 8.69 (m, 1H), 10.82 (s, 1H).

Step D

The nitro-compound (1.35 g, 3.79 mmol) from Step C was dissolved in methanol (60 mL) and stirred with 10% Pd/C under a hydrogen gas atmosphere over night. The reaction mixture was filtered through Celite and washed thoroughly with methanol. Finally, the filtrate was concentrated in vacuo and purified by column chromatography (dichloromethane/methanol=20/1) to yield the desired product (1.10 g, 89%). ¹H NMR (300 MHz, d₆-DMSO) 3.50-385 (m, 8H), 6.47 (dd 1H), 6.74 (m, 2H), 7.59 (dd, 1H), 7.71 (d, 1H), 8.04 (dd, 1H), 8.68 (d, 1H).

Preparative Example 98

Step A

1-Methyl-2-pyrrolecarboxylic acid (2.5 g, 20.0 mmol) was dissolved in dichloromethane (50 mL). After addition of PyBrOP (16.3 g, 35.0 mmol), diisopropylethylamine (14.0 mL, 73.0 mmol) and Boc-piperazine (5.5 g, 30.0 mmol), the reaction was stirred over night at room temperature before being put into 1N sodium hydroxide (200 mL). Extraction with dichloromethane (2×100 mL) removed all PyBrOP by-products. The aqueous phase was acidified with 3N HCl. Adjustment of the pH with saturated sodium carbonate solution to almost neutral precipitated the desired compound. The aqueous phase was subsequently extracted with dichloromethane (3×100 mL). The combined organic phases of the neutral extraction were dried over sodium sulfate. Removal of the solvent resulted in sufficiently pure product that was used in Step B without any further purification. ¹H NMR (300 MHz, d₆-DMSO) 1.59 (s, 9H) 3.21 (dd, 4H), 3.61 (dd, 4H), 3.74 (s, 3H), 6.11 (dd, 1H), 6.33 (d, 1H), 7.01 (d, 1H).

Step B

The crude material from Step A was dissolved in trifluoroacetic acid/dichloromethane (75 mL, 4/1). After stirring for 3 h, the reaction mixture was put into 1N sodium hydroxide (400 mL). Extraction with dichloromethane (3×100 mL) and drying over sodium sulfate resulted in sufficiently pure product that was used in Step C without any further purification. ¹H NMR (300 MHz, d₆-DMSO) 2.79 (dd, 4H), 3.62 (dd, 4H), 3.76 (s, 3H), 6.11 (dd, 1H), 6.37 (dd, 4H), 6.96 (d, 1H).

Step C

The crude material (3.15 g, 16.3 mmol) from Step B was dissolved in dichloromethane (100 mL). After addition of diisopropylethylamine (8.5 mL, 49.0 mmol), 3-nitrosalicylic acid (3.13 g, 17.1 mmol), and PyBrOP (9.11 g, 19.6 mmol), the resulting mixture was stirred over night at room temperature before being put into 1N sodium hydroxide (400 mL). Extraction with dichloromethane (2×100 mL) removed all PyBrOP products. The aqueous phase was then carefully acidified with 3N HCl until the color of the solution changes from orange to yellow and the desired compound crashed out of solution. The aqueous phase was subsequently extracted with dichloromethane (3×100 mL). The combined organic layers of the acidic extraction were dried over sodium sulfate and concentrated in vacuo to yield the desired product. ¹H NMR (300 MHz, d₆-DMSO) 3.35-3.85 (m, 8H), 3.79 (s, 3H), 6.13 (dd, 1H), 6.45 (d, 1H), 7.01 (s, 1H), 7.22 (dd, 1H), 7.70 (d, 1H), 8.16 (d, 1H), 10.83 (s, 2H).

Step D

The crude nitro-compound from Step C was suspended in methanol (60 mL) and stirred with 10% Pd/C under a hydrogen gas atmosphere over night. The reaction mixture was filtered through Celite and washed thoroughly with methanol. The filtrate was concentrated in vacuo and purified by column chromatography (dichloromethane/methanol=10/1) to yield the desired product (2.61 g, 40% for 4 steps). ¹H NMR (300 MHz, d₆-DMSO) 3.45-4.80 (m, 8H), 3.79 (s, 3H), 6.17 (dd, 1H), 6.45 (m, 2H), 6.78 (m, 2H), 7.01 (d, 1H).

Preparative Example 99

Step A

2-Bromopyridine N-oxide hydrochloride (1.13 g, 5.37 mmol) and Boc-piperazine (1.50 g, 8.06 mmol) were heated to 80° C. in pyridine (10 mL) over night. The reaction mixture was put into water (30 mL) and then extracted with dichloromethane (2×100 mL). The combined organic phases were dried over sodium sulfate, concentrated, and finally purified by column chromatography (dichloromethane/methanol=10/1) to yield the desired product (500 mg, 33%).

¹H NMR (300 MHz, d-CDCl₃) 1.60 (s, 9H), 3.46 (dd, 4H), 3.78 (dd, 4H), 6.99 (m, 2H), 7.37 (dd, 1H), 8.33 (d, 1H).

Step B

The purified product (500 mg, 1.79 mmol) was stirred for 30 min with 4N HCl/dioxane (15 mL). Evaporation of the solvent yielded the crude amine (465 mg) as multiple HCl-salt which was used in Step C without any further purification.

¹H NMR (300 MHz, d₆-DMSO) 3.38 (m, 4H), 4.81 (m, 4H), 7.34 (dd, 1H), 7.55 (d, 1H): 7.86 (dd, 1H), 8.55 (d, 1H).

Step C

The crude material (370 mg, 1.48 mmol) from Step B was suspended in dichloromethane (20 mL). After addition of diisopropylethylamine (2.6 mL, 14.8 mmol), 3-nitrosalicylic acid (406 mg, 2.22 mmol), and PyBrOP (1.21 g, 2.59 mmol), the mixture was stirred over night at room temperature before being put into 1N sodium hydroxide (50 mL). Extraction with dichloromethane (2×50 mL) removed all PyBrOP products. The aqueous phase was then carefully acidified (pH ˜4-5) with 3N HCl and extracted with dichloromethane (3×50 mL). The combined organic layers of the acidic extraction to were dried over sodium sulfate concentrated in vacuo and purified by column chromatography (dichloromethane/methanol=10/1) to yield the desired product (330 mg, 65%).

LCMS calculated: 344.1. found: (M+1)⁺ 345.1.

Step D

Sodium hydrosulfite (1.05 g) was dissolved in water (3.0 mL) to yield a 1.5N solution. Addition of dioxane (3.0 mL) was followed by injection of conc. ammonium hydroxide (0.60 mL, yields a 1.0N concentration). After addition of the nitro-compound (100 mg, 0.29 mmol), the reaction mixture was stirred for 0.5 h. Subsequently, the solvent was removed and the residue suspended in dichloromethane/methanol (10/1). Filtration through Celite removed most of the salts. Final purification by column chromatography (dichloromethane/methanol=5/1) yielded the desired product (68 mg, 75%).

LCMS calculated: 314.14. found, (M+1)⁺ 315.1

Preparative Example 100

Step A

4-Bromopyridine hydrochloride (3.0 g, 15.4 mmol) was dissolved in water (15 mL). After addition of N-benzylpiperazine (14.8 mL, 85.0 mmol) and 500 mg copper sulfate, the reaction mixture was heated overnight to 140° C. The resulting product was extracted with ether (5×75 mL), dried over sodium sulfate and concentrated. Final purification by column chromatography (dichloromethane/methanol/NH₄OH=10/1/0.1) yielded the desired product (2.16 g, 55%). ¹H NMR (300 MHz, d-CDCl₃) 2.68 (dd, 4H), 3.45 (dd, 4H), 6.76 (d, 2H), 7.40 (m, 5H), 8.38 (d, 2H).

Step B

The benzylamine (2.16 g, 8.54 mmol) from Step A, ammonium formate (2.71 g, 43.0 mmol) and Pd(C) (10%, 1.0 g) was suspended in methanol (50 mL) and refluxed for 3 h. The palladium was filtered off and the filtrate was concentrated. The sufficiently pure product was used in Step C without any further purification. ¹H NMR (300 MHz, d-CDCl₃) 2.48 (bs, 1H), 3.13 (dd, 4H), 3.41 (dd, 4H), 7.78 (d, 2H), 8.39 (d, 2H).

Step C

The crude material (1.15 g, 7.06 mmol) from Step B was dissolved in dichloromethane (50 mL). After addition of diisopropylethylamine (4.7 mL, 42.4 mmol), 3-nitrosalicylic acid (1.94 g, 10.6 mmol), and PyBrOP (5.78 g, 12.3 mmol), the resulting mixture was stirred over night at room temperature before being put into 1N sodium hydroxide (30 mL). Extraction with dichloromethane (2×100 mL) removed all PyBrOP products. The aqueous phase was carefully acidified to pH ˜5-6 with 3N HCl and extracted with dichloromethane (3×100 mL). The combined organic layers of the neutral extraction were dried over sodium sulfate, concentrated, and finally purified by column chromatography (dichloromethane/methanol/NH₄OH=10/1/0.1) to yield the desired product (850 mg, 37% for 2 steps).

Step D

The nitro-compound (850 mg, 2.59 mmol) from Step C was dissolved in methanol (40 mL) and stirred with 10% Pd/C under a hydrogen gas atmosphere over night. The reaction mixture was filtered through Celite and washed thoroughly with methanol. Finally, the filtrate was concentrated in vacuo and purified by column chromatography (dichloromethane/methanol/NH₄OH=10/1/0.1) to yield the desired product (650 g, 84%). ¹H NMR (300 MHz, d₆-DMSO) 3.40-3.75 (bm, 8H), 6.49 (dd, 1H), 6.76 (m, 2H), 6.93 (d, 2H), 8.28 (d, 2H).

Preparative Example 101

Step 1

N,N′-Dibenzyl-ethane-1,2-diamine (20 mL, 0.0813 mol), triethylamine (22.66 mL, 0.1626 mol) and benzene (100 mL) were combined in a round bottom flask. A solution of 2,3-dibromo-propionic acid ethyl ester (11.82 mL, 0.0813 mol) in benzene (50 mL) was added dropwise. The solution was refluxed over night and monitored by TLC (20% ethyl acetate/hexane). The reaction was cooled to room temperature, then filtered and washed with benzene. The filtrate was concentrated then purified by column chromatography (15% ethyl acetate/hexane). The product was isolated as an oil (25.42 g, 0.0752 mol, 92%). MS: calculated: 338.20. found: 339.2. ¹H NMR (300 MHz, CDCl₃) 1.23 (t, 3H), 2.48 (m, 1H), 2.62 (m, 1H), 2.73 (m, 1H), 3.07 (m, 1H), 3.30 (m, 1H), 3.42 (d, 1H), 3.56 (m, 2H), 3.91 (d, 1H), 4.17 (m, 2H), 7.27 (m, 10H).

Step 2

In a Parr shaker vessels the ester (25.43 g, 0.075 mol) and methanol (125 mL) were combined. The vessel was purged with argon and palladium catalyst (5% on carbon, 2.5 g) was added. The system was shaken under an atmosphere of hydrogen overnight. TLC (20% ethyl acetate/hexane) indicated that reaction was complete. The reaction mixture was filtered through a pad of Celite and washed with methanol. The filtrate was concentrated and the product isolated as a solid (11.7 g, 0.074 mol, 98%).

MS: calculated: 158.11. found: 159.2. ¹H NMR (300 MHz, CDCl₃) 1.27 (t, 3H) 2.70 (m, 4H), 2.96 (m, 1H), 3.13 (dd, 1H), 3.43 (dd, 1H), 4.18 (m, 2H).

Preparative Example 102

Piperazine-2-carboxylic acid ethyl ester (3.11 g, 0.0197 mol), diisopropylethylamine (5.15 mL, 0.0296 mol) and methylene chloride (200 mL) were combined in a round bottom flask. While stirring at room temperature, a solution of N,N-dimethylcarbamoyl chloride (1.81 mL, 0.0197 mol) in methylene chloride (20 mL) was added dropwise. The reaction was stirred for one hour. After this time the reaction was concentrated and carried on to the next step without further purification. (99% yield),

MS: calculated: 229.14. found: 230.1. ¹H NMR (300 MHz, CDCl₃) 1.30 (t, 3H), 2.85 (s, 6H), 3.10 (m, 3H), 3.31 (m, 2H), 3.60 (m, 2H), 4.21 (q, 2H).

Preparative Example 103-104

Following the procedure described for Preparative Example 102, the Products listed in the table below were prepared using the commercially available chloride shown and piperazine-2-carboxylic acid ethyl ester from Preparative Example 101.

Ex- 1. Yield (%) ample Chloride Product 2. (M + 1)⁺ 103

1. 99 2. 237.1 104

1. 62 2. 253.1

Preparative Example 105

Step 1

3-Nitrosalicylic acid (3.61 g, 0.0197 g), DCC (2.03 g, 0.0099 mol) and ethyl acetate (130 mL) were combined in a round bottom flask and stirred for 15 min. 4-Dimethylcarbamoyl-piperazine-2-carboxylic acid ethyl ester (4.51 g, 0.0197 g) was added, and the reaction was stirred for 72 hours. The reaction mixture was concentrated then dissolved in dichloromethane. The organic phase was washed to once with 0.1N sodium hydroxide. The aqueous phase was back extracted once with dichloromethane. The aqueous phase was acidified and wash three times with ethyl acetate. The aqueous phase was concentrated and purified by column chromatography (5% methanol/DCM).

MS: calculated. 394.15. found: 395.0. ¹H NMR (300 MHz, CDCl₃) 1.32 (t, 3H), 2.86 (m, 7H), 3.15 (m, 1H), 3.51 (m, 4H), 4.24 (m, 3H), 7.15 (m, 1H), 7.66 (m, 1H), 8.20 (m, 1H), 10.86 (bs, 1H).

Step 2

4-Dimethylcarbamoyl-1-(2-hydroxy-3-nitro-benzoyl)-piperazine-2-carboxylic acid ethyl ester (0.80 g, 0.002 mol) and methanol (50 mL) were combined in a round bottom flask. The system was purged with argon. To the solution was added 5% palladium on carbon (˜100 mg). The flask was purged with hydrogen and stirred overnight. The reaction was filtered through a pad of celite and washed with methanol. The material was concentrated then purified by column chromatography (6% methanol/DCM). Isolated product (0.74 g, 0.002 mol, 100%).

MS: calculated: 364.17. found: 365.1. ¹H NMR (300 MHz, CDCl₃) 1.27 (t, 3H), 2.85 (m, 8H), 3.18 (1H), 3.45 (m, 3H), 4.19 (m, 3H), 3.90 (m, 3H)

Step 3

1-(3-Amino-2-hydroxy-benzoyl)-4-dimethylcarbamoyl-piperazine-2-carboxylic acid ethyl ester (0.74 g, 0.002 mol) was suspended in a solution of dioxane (10 mL) and water (10 mL). Lithium hydroxide (0.26 g, 0.0061 mol) was added and the mixture stirred for two hours. The solution was acidified to pH=6 with 3N HCl then extracted with butanol. The extracts were combined, dried over sodium sulfate and concentrated.

MS: calculated: 336.14. found: 337.1. ¹H NMR (300 MHz, CD₃OD) 2.86 (m, 7H), 3.23 (m, 3H), 3.54 (m, 3H), 6.92 (m, 2H), 7.23 (m, 1H).

Preparative Example 106-107

Following the procedure described for Example 105, the Products listed in the table below were prepared using the amine from the Preparative Example indicated and 3-nitrosalacylic acid.

1. Yield (%) 2. (M + 1)⁺ Example Aniline Product 3. Note 106 103

1. 91 2. Not observed 3. Rainey nickel used in Step 2 107 104

1. 24 2. 360.0 3. For Step 1 used PyBrop/ DIEA in DCM

Preparative Example 108

Step A

3-Nitrosalicylic acid (1.0 g, 5.5 mmol) was dissolved in ethyl acetate (20 mL). 1,3-Dicyclohexylcarbodiimide (0.568 g, 2.8 mmol) was added and the mixture was stirred for approximately 10 minutes and cooled to 0° C. During this time a precipitate formed. Azetidine (0.39 mL, 5.8 mmol) was added and the reaction was stirred overnight and allowed to warm to room temperature. After this time the reaction was cooled to 0° C. and filtered. The collected solid was washed with chilled ethyl acetate. The filtrate was concentrated and purified by column chromatography (80% EtOAc/Hex) to give the product (476 mg, 39.0%).

¹H NMR (300 MHz, CDCl₃) δ2.40 (m, 2H), 4.38 (m, 4H), 6.97 (m, 1H), 7.62 (d, 1H), 8.12 (d, 1H), 12.88 (m, 1H) ppm.

Step B

The nitro compound (0.48 g, 2.1 mmol) from Preparative Example 32 Step A was dissolved in methanol (25 ml) and stirred with 10%. Pd/C under a hydrogen gas atmosphere overnight. The reaction mixture was filtered through celite, the filtrate concentrated in vacuo to give the product (344 mg, 90%). ¹H NMR (300 MHz, CDCl₃) δ2.52 (m, 2H), 4.57 (bs, 4H), 6.75 (m, 1H), 6.90 (m, 2H), 12.71 (bs, 1H) ppm.

Preparative Example 109

In essentially the same manner as described in Preparative Example 108 above, the morpholino-amine product was obtained.

Preparative Example 110

Piperazine (4.9 g, 0.057 mol) was dissolved in dichloromethane (100 mL). N,N′-Dimethylcarbamoyl chloride (1.0 mL, 0.011 mol) was added dropwise to the solution at room temperature. The reaction was stirred for one hour. After this time 1N potassium hydroxide (200 mL) was added. The layers were separated and the aqueous layer was extracted three times with dichloromethane. The organic fractions were combined and dried over sodium sulfate. Filtration and concentration provided the product, without further purification, as an oil (1.16 g, 13%).

¹H NMR (CDCl₃, 300 MHz) 1.95 (s, 1H), 2.83 (s, 6H), 2.86 (m, 4H), 3.20 (m, 4H). MS: calculated: 157.12. found: 158.1.

Preparative example 111

Piperazine (4.9 g, 0.057 mol) was dissolved in 1N HCl (100 mL). A solution of phenylsulfonylchloride (1.45 mL, 0.011 mol) in acetonitrile (25 mL) was added dropwise to the solution at room temperature. The reaction was stirred for 30 minutes. After this time the reaction was extracted two times with ethyl acetate. The solution was then made basic with 1N potassium hydroxide and extracted three times with dichloromethane. The dichloromethane fractions were combined and dried over magnesium sulfate. Filtration and concentration provided the product, without further purifications as a solid (1.22 g, 9.4%).

¹H NMR (CDCl₃, 300 MHz) 2.94 (m, 8H), 7.56 (m, 3H), 7.76 (m, 2H). MS: calculated: 226.08. found: 227.1.

Preparative Example 112

Piperazine (4.9 g, 0.057 mol) was dissolved in dichloromethane (100 mL). Methanesulfonyl chloride (0.85 mL 0.011 mol) was added dropwise to the solution at room temperature. The reaction was stirred for 30 minutes. After this time 1N potassium hydroxide (200 mL) was added. The layers were separated and the aqueous layer was extracted three times with dichloromethane. The organic fractions were combined and dried over sodium sulfate. Filtration and concentration provided the product, without further purification, as a solid (1.07 g, 11%).

¹H NMR (CDCl₃, 300 MHz) 1.75 (s, 1H), 2.78 (s, 3H), 2.97 (m, 4H), 3.20 (m, 4H). MS: calculated: 164.06. found: 165.1.

Preparative Example 113

Step A

Boc-piperazine (3.0 g, 0.0161 mol) was dissolved in dichloromethane (100 mL). Propylisocyanate (1.51 mL, 0.0161 mol) was added to the solution at room temperature. The reaction was stirred for over night. After this time the reaction was diluted with 1N potassium hydroxide (200 mL) and extracted six times with dichloromethane. The organic fractions were combined and dried over magnesium sulfate. Filtration and concentration provided the product as a solid.

Step B

The product of Step A above, was dissolved in a 30% trifluoroacetic acid/dichloromethane solution and stirred overnight. After this time a 1N potassium hydroxide solution (200 mL) was added to the reaction. The aqueous layer was extracted a total of six times with dichloromethane. The organic fractions were combined and dried over sodium sulfate. Filtration and concentration provided the product (1.37 g, 50%).

¹H NMR (CDCl₃, 300 MHz) 0.92 (t, 3H), 1.52 (m, 2H), 2.89 (m, 4H), 3.01 (s, 1H), 3.18 (m, 2H), 3.37 (m, 4H), 4.61 (bs, 1H). MS: calculated: 171.14. found: 172.0.

Preparative Example 114

Piperazine (4.9 g, 0.0569 mol) was dissolved in 1N HCl (70 mL). A solution of phenylchloroformate (1.43 mL, 0.0114 mol) in acetonitrile (25 mL) was added dropwise to the solution at room temperature. The reaction was stirred for 30 minutes. After this time the reaction was extracted two times with ethyl acetate. The solution was then made basic with 1N potassium hydroxide and extracted three times with dichloromethane. The dichloromethane fractions were combined and dried over magnesium sulfate. Filtration and concentration provided the product, without further purification, as a solid (2.12 g, 18%).

¹H NMR (CDCl₃, 300 MHz) 1.78 (s, 1H), 2.91 (m, 4H), 3.59 (m, 4H), 7.11 (2H), 7.19 (m, 1H), 7.36 (m, 2H). MS: calculated. 206.24. found: 207.1.

Preparative Example 115-117

Following the procedure described for Example 112, the Products listed in the table below were prepared using the commercially available chloroformate shown and piperazine.

1. Yield (%) Example Chloromate Product 2. (M + 1)⁺ 115

1. 54 2. 144.9 116

1. 17 2. 173.0 117

1. 69 2. 173.0

Preparative Example 118

Step A

Boc-piperazine (3.01 g, 0.0161 mol) was dissolved in dichloromethane (100 mL) along with diisopropylethylamine (5.61 mL, 0.0322 mol). Benzoylchloride (1.87 mL, 0.0161 mol) was added dropwise to the solution at room temperature. The reaction was stirred for several hours. After this time the reaction was concentrated and the product was purified by column chromatography (10% MeOH/DCM). Boc-Protected product was isolated as a solid (5.21 g).

¹H NMR (CDCl₃, 300 MHz) 1.47 (s, 9H), 3.45 (m, 8H), 7.41 (m, 5H). MS: calculated: 290.16. found: 290.8.

Step B

The product from Step A above, was dissolved in a 50% trifluoroacetic acid/dichloromethane solution and stirred overnight. After this time the reaction was diluted with 1N potassium hydroxide (200 mL) and the organic layer was separated. The aqueous phase was then extracted six times with dichloromethane. The organic fractions were combined and dried over magnesium sulfate. Filtration and concentration provided product (2.93 g).

¹H NMR (CDCl₃, 300 MHz) 1.92 (s, 1H), 2.87 (m, 4H), 3.52 (m, 4H), 7.39 (s, 5H). MS: calculated: 190.11. found: 191.1.

Preparative Example 119

Step A

Boc-piperazine (3.0 g, 0.0161 mol) was dissolved in dichloromethane (100 mL) along with disopropylethylamine (3.1 mL, 0.0177 mol). N,N′-dimethylsulfamoyl chloride (1.73 mL, 0.0161 mol) was added dropwise to the solution at room temperature. The reaction was stirred for several hours. After this time the reaction was diluted with water (100 mL). The layers were separated and the aqueous layer was extracted six times with dichloromethane. The organic fractions were combined and dried over magnesium sulfate. Filtration and concentration provided the product, without further purification, as a solid (4.53 g).

¹H NMR (CDCl₃, 300 MHz) 1.47 (s, 9H), 2.84 (s, 6H), 3.21 (m, 4H), 3.48 (m, 4H). MS: calculated: 293.14. found: 194.1 (M−Boc)⁺.

Step B

The product from Step A above, was dissolved in a 30% trifluoroacetic acid/dichloromethane solution and stirred overnight. After this time the reaction was diluted with water and 1N potassium hydroxide was used to make the aqueous layer slightly basic. The aqueous layer was extracted a total of seven times with dichloromethane. The organic fractions were combined and dried over sodium sulfate. Filtration and concentration provided the product (2.96 g).

¹H NMR (CDCl₃, 300 MHz) 2.03 (s, 1H) 2.83 (s, 6H). 2.92 (m, 4H), 3.23 (m, 4H). MS: calculated: 193.09. found: 194.1.

Preparative Example 120 Step A

In essentially the same manner as that described in Preparative Example 105, Step 1, using 3-nitrobenzoic acid instead of 3-nitrosalicylic acid, the methyl ester product was prepared.

Step B

The methyl ester (1.79 g, 6.1 mmol) from Step A above, was dissolved in dioxane/water (20 mL/15 mL) at room temperature. Lithium hydroxide (0.258 g, 6.2 mmol) was added to the solution. After a few hours more lithium hydroxide was added (0.128 g, 3.0 mmol) and the reaction was stirred for another hour. After this time the reaction was concentrated and then taken up in water. The solution was extracted two times with ether. The aqueous phase was then acidified and extracted three times with ethyl acetate. The organic fractions were then dried over sodium sulfate, filtered and concentrated. Product was isolated by column chromatography (95% EtOAc/Hex, 0.05% HOAc) to give the product (1.66 g, 98%).

¹H NMR (300 MHz, CDCl₃) 1.49 (m, 2H), 1.68 (m, 1H), 1.12 (m, 2H), 2.44 (m, 1H) 3.32 (m, 1H), 3.58 (m, 1H), 5.57 (m, 1H), 7.65 (m, 1H), 7.80 (m, 1H), 8.32 (m, 2H), 10.04 (bs, 1H) ppm.

Step C

The nitro compound was dissolved in an excess of methanol (20 mL) and covered by a blanket of argon. 5% Palladium on carbon was added (catalytic) and a hydrogen balloon was attached to the flask. The atmosphere of the system was purged under vacuum and replaced with hydrogen. This step was repeated for a total of three times. The reaction was then stirred under hydrogen overnight. After this time the balloon was removed and the solution was filtered through celite followed by several rinses with methanol. The filtrate was concentrated and dried on the vacuum line to provide the desired aniline product (1.33 g, 90%),

¹H NMR (300 MHz, CDCl₃) 1.40 (m, 2H), 1.50 (m, 1H), 1.68 (m, 2H), 2.33 (m, 1H) 3.18 (m, 1H), 3.62 (m, 1H), 5.39 (m, 1H), 6.12 (bs, 2H), 6.75 (m, 2H), 7.12 (m, 1H) ppm. Mass Spectra, calculated: 248. found: 249.1 (M+1)⁺

Preparative Examples 121-123

Following the procedure described in Preparative Example 120, but using the commercially available amine and benzoic acid indicated, the intermediate products in the table below were obtained.

1. Yield (%) Prep Carboxylic 2. (M + 1)⁺ Ex Acid Amine Product 3. Note 121

1. 21 2. 251.0 122

1. 21 2. 265.0 3. Skipped step B 123

1. 15 2. 264.0 3. Skipped step B

Preparative Example 124

Step A

3-Nitrosalicylic acid (500 mg, 2.7 mmol), 1,3-dicyclohexylcarbodiimide (DCC) (563 mg) and ethyl acetate (10 mL) were combined and stirred for 10 min, (r)-(−)-2-pyrrolidinemethanol (0.27 mL) was added and the resulting suspension was stirred at room temperature overnight. The solid was filtered off and the filtrate was either concentrated down and directly purified or washed with 1N NaOH. The aqueous phase was acidified and extracted with EtOAc. The resulting organic phase was dried over anhydrous MgSO₄, filtered and concentrated in vacuo. Purification of the residue by preparative plate chromatography (silica gel, 5% MeOH/CH₂Cl₂ saturated with AcOH) gave the desired compound (338 mg, 46%, MH⁺=267).

Step B

The product from Step A above was stirred with 10% Pd/C under a hydrogen gas atmosphere overnight. The reaction mixture was filtered through celite, the filtrate concentrated in vacuo, and the resulting residue purified by column chromatography (silica gel, 4% MeOH/CH₂Cl₂ saturated with NH₄OH) to give the product (129 mg, 43%, MH+=237).

Preparative Examples 125-145

Following the procedure described for Preparative Example 124, but using the commercially available amine or the amine from the Preparative Example indicated and 3-nitrosalicylic acid, the products in the table below were obtained.

Amine Prep Comm. Avail./ 1. Yield (%) Ex From Prep. Ex. Product 2. (M + 1)⁺ 125

1. 37 2. 298.1 126

1. 31 2. 310.1 127

1. 68 2. 294.1 128

1. 54 2. 365.9 129

1. 45 2. 316.1 130 110

1. 59 2. 293.1 131 111

1. 32 2. 362.0 132 114

1. 36 2. 342.0 133 112

1. 65 2. 300.0 134

1. 48 2. 321.1 135

1. 50 2. 300.1 136

1. 56 2. 299.2 137 115

1. 79 2. 280.1 138 116

1. 64 2. 307.1 139

1. 73 2. 304.2 140

1. 34 2. 264.0 141 117

1. 40 2. 307.1 142 113

1. 91 2. 307.1 143 118

1. 9.0 2. 326.0 144 119

1. 42 2. 329.0 145

1. 6.5 2. 236.1

Preparative Example 146

step A

To a solution of tosylaziridine (J. Am. Chem. Soc. 1998, 120, 6844-6845, the disclosure of which is incorporated herein by reference thereto) (0.5 g, 2.1 mmol) and Cu(acac)₂ (55 mg, 0.21 mmol) in THF (5 mL) at 0° C. was added PhMgBr (3.5 ml, 3.0 M in THF) diluted with THF (8 mL) dropwise over 20 min. The resulting solution was allowed to gradually warm to rt and was stirred for 12 h. Sat. aq. NH₄Cl (5 mL), was added and the mixture was extracted with Et₂O (3×15 mL). The organic layers were combined, washed with brine (1×10 mL), dried (MgSO₄) and concentrated under reduced pressure. The crude residue was purified by preparative TLC eluting with hexane/EtOAc (4.1) to afford 0.57 g (86% yield) of a solid. The purified tosylamine was taken on directly to the next step.

Step B

To a solution of tosylamine (0.55 g, 1.75 mmol) in NH₃ (20 mL) at −78° C. was added sodium (0.40 g, 17.4 mmol). The resulting solution was stirred at −78° C. for 2 h whereupon the mixture was treated with solid NH₄Cl and allowed to warm to rt. Once the NH₃ had boiled off, the mixture was partitioned between water (10 mL) and CH₂Cl₂ (10 mL). The layers were separated and the aqueous layer was extracted with CH₂Cl₂ (2×10 mL). The organic layers were combined), dried (NaSO₄), and concentrated under reduced pressure to a volume of ˜20 mL. 4N HCl in dioxane (5 mL) was added and the mixture was stirred for 5 min. The mixture was concentrated under reduced pressure and the resultant crude residue was recrystallized from EtOH/Et₂O to afford 0.30 g (87% yield) of a solid.

Preparative Examples 147-156.10

Following the procedure set forth in Preparative Example 146 but using the requisite tosylaziridines and Grignard reagents listed in the Table below, the following racemic amine hydrochloride products were obtained.

Prep. Tosyl Grignard Amine Yield Ex. aziridine Reagent hydrochloride (%) 147

MeMgBr

1.19% 148

EtMgBr

1.56% 149

n-PrMgBr

1.70% 150

i-PrMgCl

1.41% 151

BnMgCl

1.61% 152

MeMgBr

1.61% 153

EtMgBr

1.66% 154

n-PrMgBr

1.80% 155

i-PrMgBr

1.27% 156

BnMgCl

1.79% 156.1

52 156.2

49 156.3

61 156.4

57 156.5

64 156.6

64 156.7

45 156.8

23 156.9

40 156.10

15

Preparative Example 156.11

Step A

To a solution of the amine (118 mg) from Preparative Example 148 in CH₂Cl₂ (10 ml) was added triethylamine (120 ul), R-Mandelic Acid (164 mg), DCC (213 mg) and DMAP (8.8 mg) and let stir for 40 hr. The mixture was diluted with CH₂Cl₂ and washed with saturated ammonium chloride, dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude material was purified by preparative plate chromatography (Hex/EtOAc 4:1) to afford both isomers (A, 86 mg, 45%) (B, 90 mg, 48%).

Step B

To isomer B (90 mg) from above in dioxane (5 ml) was added 6M H₂SO₄ (5 ml). The reaction was heated to 80° C. over the weekend. 2M NaOH added to basify the reaction and extracted with ether. Ether layer washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was stirred in 4N HCl in dioxane for 30 min, concentrated in vacuo and recrystallized in EtOH/ether to afford 65 mg of product (98%).

Step C

Isomer A (86 mg) was reacted following the procedure set forth in Step B above to give the amine salt.

Preparative Example 156.12

The above nitro compound was reduced following the Preparative Example 2, Step B.

Preparative Example 156.13

To a solution of 1,2-phenylenediame (1.5 g) in CH₂Cl₂ (30 ml) at 0° C. was added TEA (2.91 ml), followed by dropwise addition of MeSO₂Cl (1.07 ml). The mixture was allowed to warm to room temperature and stir overnight. 1M HCl added and the layers were separated. The aqueous layer was adjusted to pH=11 with solid NaOH, extracted with CH₂Cl₂. The basified aqueous layer was then neutralized using 3N HCl and extracted with CH₂Cl₂, dried with Na₂SO₄, filtered, and concentrated in vacuo to give 1.8 g of product (71%).

Preparative Example 156.14

The above compound was prepared using the procedure set forth in Preparative Example 156.13, but using PhSO₂Cl.

Preparative Example 156.15

The nitro compound was reduced following a similar procedure as in Preparative Example 2, Step B.

Preparative Example 156.16

Step A

The known acid (410 mg) above (J. Med. Chem. 1996, 34, 4654, the disclosure of which is incorporated herein by reference thereto) was reacted following the procedure set forth in Preparative Example 2, Step A to yield 380 mg of an oil (80%).

Step B

The amide (200 mg) from above was reacted following the procedure set forth in Preparative Example 2, Step B to yield 170 mg of an oil (100%).

Preparative Example 156.17

Step A

To a solution of ketone (500 mg) in EtOH/water (3:1, 4 ml) at room temperature was added hydroxylamine hydrochloride (214 mg) followed by NaOH to afford a heterogenous mixture. The reaction was not complete so another equivalent of hydroxylamine hydrochloride was added and refluxed overnight. The reaction was cooled to 0° C. and treated with 3N HCl and extracted with CH₂Cl₂, washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo to give 500 mg of product (92%).

Step B

To a solution of oxime (300 mg) in THF (5 ml) at 0° C. was added LiAlH₄ (266 mg) portionwise. The heterogenous solution was stirred at room temperature for 14 hr and then refluxed for 8 hr. The solution was cooled to 0° C. and water, 2M NaOH, water and ether were added to the reaction. The mixture was filtered through a celite pad. The filtrate was treated with 3N HCl. The aqueous layer was cooled to 0° C., basified with NaOH pellets and extracted with ether. The ether layer was dried over MgSO₄, filtered, and concentrated in vacuo to afford the product (143 mg, 69%).

Preparative Example 156.18

Step A

Methoxyacetic acid (14 mL) in CH₂Cl₂ (120 mL) and cooled in an ice-water bath was treated with DMF (0.9 mL) and oxalyl chloride (21 mL). After stirring at RT overnight, the mixture was concentrated in vacuo and redissolved in CH₂Cl₂ (120 mL) N-methyl-N-methoxylamine (20 g) was added and the mixture stirred at RT overnight. Filtration and concentration in vacuo afforded the desired amide (21 g, 89%).

Step B

To a solution of the above amide (260 mg) in THF (5 ml) at −78° C. was added a solution of 2-thienyllithium (1M in THF, 2.15 ml). The solution was stirred for 2 hr at 78° C. and warmed to −20° C. for an additional 2 hr. The reaction was quenched with saturated ammonium chloride and extracted with CH₂Cl₂, washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo to give 250 mg of product (82%).

Step C

The ketone from above (250 mg) was reacted via the procedure set forth in Preparative Example 156.17 Steps A and B to yield 176 mg of the amine (79%).

Preparative Example 156.19

Step A

To a solution of 3-chlorothiophene (1.16 ml) in ether (20 ml) at −10° C. was added n-BuLi (2.5M in hexane, 5 ml). After solution was stirred at −10° C. for 20 min, propionaldehyde (0.82 ml) in ether (20 ml) was added dropwise and let warm to room temperature slowly. The reaction was quenched with saturated ammonium chloride and extracted with CH₂Cl₂ washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo to give 1.37 g of product (62%).

Step B

The alcohol from Step A above was reacted via the procedures set forth in Preparative Example 75.75, Steps B and C to give the amine.

Preparative Example 156.20

Step A

To a solution of magnesium metal (360 mg) in THF (15 ml) at 0° C. was added 2-bromothiophene (1.45 ml) in THF (10 ml) dropwise over 20 min. The solution was warmed to room temperature for 3 hr, recooled to 0° C. whereupon a solution of cyclopropylacetonitrile (1 g) in ether (30 ml) was added dropwise via a syringe and let warm to room temperature and stir overnight. 3M HCl was added and washed with CH₂Cl₂. The aqueous layer was basified with NaOH pellets and extracted with ether, dried with Na₂SO₄, filtered, and concentrated in vacuo to give 625 mg of product (68%).

Step B

The ketone was reacted via the procedure set forth in Preparative Example 156.17 Step A to give the oxime.

Step C

The oxime from above was reacted via the procedure set forth in Preparative Example 156.17 Step B to give the amine.

Preparative Example 15621

Step A

To a solution of CH₃ONHCH₃.HCl (780 mg) and acid chloride (1 g) in CH₂Cl₂ at 0° C. was added dry pyridine (1.35 ml) to afford a heterogenous mixture The solution was warmed to room temperature and stirred overnight. 1M HCl was added to the reaction and the organic layer was separated, washed with brine, dried with Na₂SO₄, filtered, and concentrated in vacuo to give 1 g of product (85%).

Step B

To a solution of EtI (614 ul) in ether (5 ml) at −78° C. was added t-BuLi (1.7M in pentane, 9 ml) dropwise. The mixture was warmed to room temperature for 1 hr, cooled to −78° C. where the amide (1 g) from Step A in THF (4 ml) was added and allowed to warm to 0° C. for 2 hr. 1M HCl was added to the reaction and extracted with CH₂CO₂, washed with brine, dried with Na₂SO₄, filtered, and concentrated in vacuo to give 500 mg of product (63%).

Step C

To a solution of ketone (800 mg) in THF/water (10:1, 20 ml) at 0° C. was added sodium borohydride (363 mg) portionwise. The solution was stirred for 2 hr at 0° C. The mixture was concentrated in vacuo, the residue was dissolved in CH₂Cl₂, washed with 1N NaOH and brine, dried with Na₂SO₄, filtered, and concentrated in vacuo to give 560 mg of product (69%).

Step D

The alcohol from above was reacted via the procedures set forth in Preparative Example 75-75, Steps B and C to give the amine (176 mg, 59%).

Preparative Example 156.22

Step A

Cyclopropylacetonitrile (12 mmol) in Et₂O (50 mL) at 0° C. was treated with PhMgBr (14 mmol) and the mixture was stirred for 2 hrs at 0° C., then at RT overnight, Hydrochloric acid (3 A4) was added, and after stirring for an additional 12 hrs, the mixture was extracted with CH₂Cl₂, washed with brine, dried over Na₂SO₄₁ filtered and concentrated in vacuo to give the desired ketone (1.34 g, 70%).

Step B

Following the procedures set forth in Preparative Example 156.20 Steps B and C, the amine was prepared.

Preparative Example 156.23

The above amine was prepared using the procedures set forth in WO 98/11064 (the disclosure of which is incorporated herein by reference thereto,

Preparative Example 157

Step A

By taking the known carboxylic acid (J. Med. Chem. 1996, 39, 4654-4666, the disclosure of which is incorporated herein by reference thereto) and subjecting it to the conditions outlined in Preparative Example 112, the product can be prepared.

Step B

Following a similar procedure used in Preparative Example 2, Step A, except using dimethylamine and the compound from Step A above, the product can be prepared.

is Step C

Following a similar procedure used in Preparative Example 2, Step B, except using the compound from Step B above, the product can be prepared.

Preparative Example 158

Following a similar procedure used in Preparative Example 157, Steps A-C, except using trifluoromethylsulfonylchloride in Step A above, the product can be prepared.

Preparative Examples 160-457

Following a similar procedure as that set forth in Preparative Example 22.1 but using the commercially available (or prepared amine) indicated in the Table below and using EtOH as solvent instead of MeOH, the following thiadiazoleoxide intermediates could be obtained.

Prep Ex Amine or Prep Ex of Amine Product 160

161

162

163

164

165

166

167

168

250   1316A

251 1317

252 1318

253   1205A

350

351

352

353

354

355

356

357

450   6

451   5

452  13.9

453  19.1

454  19

455   1304B

456  23.10A

457   1304A

Preparative Example 500.1

Step A

By using the nitro-amide from Preparative Example 13.3, Step A, the amidine structure can be prepared following a similar procedure to that in Tetrahedron Lett., 2000, 41 (11), 1677-1680 (the disclosure of which is incorporated herein by reference thereto).

Step B

By using the product from Step A and the procedure set forth in Preparative Example 2, Step B, one could obtain the desired amine-amidine.

Alternate Preparative Example 500.2

Step A

By treating the nitro-amide from Preparative Example 13.3, Step B with POCl₃ and subsequently MeNH₂, according to procedures known in the art, one would obtain the desired compound.

Step B

By treating the product from Step A according to the procedure set forth in Preparative Example 13.3, Step E, one could obtain the desired compound.

Step C

By using the product from Step B and the procedure set forth in Preparative Example 2 Step B, one would obtain the desired compound.

Preparative Example 500.3

Step A

By following a similar procedure as that described in Zh. Obshch. Khim., 27, 1957, 754, 757 (the disclosure of which is incorporated herein by reference thereto), but instead using 2,4-dichlorophenol and dimethylphosphinic chloride, one would obtain the desired compound.

Step B

By following a similar procedure as that described in J. Organomet Chem.; 317, 1986, 11-22 (the disclosure of which is incorporated herein by reference thereto), to one would obtain the desired compound.

Step C

By following a similar procedure as that described in J. Amer. Chem. Soc., 77, 1955, 6221 (the disclosure of which is incorporated herein by reference thereto), one would obtain the desired compound.

Step D

By following a similar procedure as that described in J. Med. Chem., 27, 1984, 654-659 (the disclosure of which is incorporated herein by reference thereto), one would obtain the desired compound,

Alternate Preparative Example 500.4

Step A

By following a similar procedure as that described in Phosphorous, Sulfur Silicon Relat. Elem.; EN; 61, 12, 1991, 119-129 (the disclosure of which is incorporated herein by reference thereto), but instead using 4-chlorophenol, one would obtain the desired compound.

Step B

By using a similar procedure as that in Phosphorous, Sulfur Silicon Relat. Elem.; EN; 61, 12, 1991, 119-129 (the disclosure of which is incorporated herein by reference thereto), but instead using MeMgBr, the desired compound could be prepared.

Step C

By following a similar procedure as that described in J. Amer. Chem. Soc., 77, 1955, 6221 (the disclosure of which is incorporated herein by reference thereto), one would obtain the desired compound.

Step D

By following a similar procedure as that described in J. Med. Chem., 27, 1984, 654-659 (the disclosure of which is incorporated herein by reference thereto), one would obtain the desired compound.

Preparative Example 500.5

By following a similar procedure as that set forth in J. Org. Chem. 1998, 63, 2824-2828 (the disclosure of which is incorporated herein by reference thereto), but using CH₃CCMgBr, one could obtain the desired compound.

Preparative Example 500.6

Step A

By following the procedure set forth in Preparative Example 13.1, Step B using 3-methoxythiophene, one could obtain the desired product.

Step B

By using the product from step A and following the procedure set forth in Preparative Example 13.19, Step E, the desired compound could be obtained.

Step C

By using the product from Step B and following the procedure set forth in Preparative Example 13.29, Step D, one could obtain the desired compound.

Step D

By using the product from Step C and following the procedure set forth in Preparative Example 13.3, Step B, the desired compound could be obtained.

Step E

By treating the product from Step D with n-BuLi at −78° C. in THF and quenching the resulting anion with CO₂ according to standard literature procedure, one could obtain the desired compound following aqueous acid work up.

Step F

By using the product from Step E and the procedure set forth in Preparative Example 13.19, Step C, one could obtain the desired compound.

Step G

By using the product from step F and following the procedure set forth in Preparative Example 13.19, Step E, the desired compound could be obtained.

Step H

By using the product from Step G and following the procedure set forth in Preparative Example 2, Step B, the desired compound could be obtained.

Preparative Example 500.7

Step A

If one were to use a similar procedure to that used in Preparative Example 13.3 Step B, except using the hydroxy acid from Bioorg. Med. Chem. Lett. 6(9), 1996, 1043 (the disclosure of which is incorporated herein by reference thereto), one would obtain the desired methoxy compound.

Step B

If one were to use a similar procedure to that used in Preparative Example 13.19 Step B, except using the product from Step A above, one would obtain the desired compound.

Step C

If one were to use a similar procedure to that used in Synth. Commun. 1980, 10, p. 107 (the disclosure of which is incorporated herein by reference thereto), except using the product from Step B above and t-butanol, one would obtain the desired compound.

Step D

If one were to use a similar procedure to that used in Synthesis, 1986, 1031 (the disclosure of which is incorporated herein by reference thereto), except using the product from Step C above, one would obtain the desired sulfonamide compound.

Step E

If one were to use a similar procedure to that used in Preparative Example 13.19 Step E, except using the product from Step D above, one would obtain the desired compound.

Preparative Example 500.8

Step A

If one were to treat the product from Step C of Example 1125 with BuLi (2.2 eq.) in THF followed by quenching of the reaction mixture with N,N,-dimethylsulfamoyl chloride (1.1 eq.) then one would obtain

Step B

If one were to use the product of Step A above and follow Step E of Preparative Example 500.7, then one would obtain the title compound.

Preparative Example 500.9

Step A

To a solution of 3-methoxythiophene (3 g) in dichloromethane (175 mL) at −78° C. was added chlorosulfonic acid (8.5 mL) dropwise. The mixture was stirred for 15 min at −78° C. and 1.5 h at room temp. Afterwards, the mixture was poured carefully into crushed ice, and extracted with dichloromethane. The extracts were washed with brine, dried over magnesium sulfate, filtered through a 1-in silica gel pad. The filtrate was concentrated in vacuo to give the desired compound (4.2 g).

Step B

The product from Step A above (4.5 g) was dissolved in dichloromethane (140 mL) and added with triethylamine (8.8 mL) followed by diethyl amine in THF (2M, 21 mL). The resulting mixture was stirred at room temperature overnight. The mixture was washed with brine and saturated bicarbonate (aq) and brine again, dried over sodium sulfate, filtered through a 1-in silica gel pad. The filtrate was concentrated in vacuo to give the desired compound (4.4 g).

Step C

The product from Step B above (4.3 g) was dissolved in dichloromethane (125 mL) and cooled in a −78° C. bath. A solution of boron tribromide (1.0 M in dichloromethane, 24.3 mL) was added. The mixture was stirred for 4 h while the temperature was increased slowly from −78° C. to 10° C. H₂O was added, the two layers were separated, and the aqueous layer was extracted with dichloro-methane. The combined organic layer and extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 3.96 g of the desired hydroxy-compound.

Step D

The product from step C above (3.96 g) was dissolved in 125 mL of dichloromethane, and added with potassium carbonate (6.6 g) followed by bromine (2 mL). The mixture was stirred for 5 h at room temperature, quenched with 100 mL of H₂O. The aqueous mixture was adjusted to pH ˜5 using a 0.5N hydrogen chloride aqueous solution, and extracted with dichloromethane. The extracts were washed with brine, dried over sodium sulfate, and filtered through a celite pad. The filtrate was concentrated in vacuo to afford 4.2 g of the desired bromo-compound.

Step E

The product from Step D (4.2 g) was dissolved in 100 mL of acetone and added with potassium carbonate (10 g) followed by iodomethane (9 mL). The mixture was heated to reflux and continued for 3.5 h. After cooled to room temperature, the mixture was filtered through a Celite pad. The filtrate was concentrated in vacuo to a dark brown residue, which was purified by flash column chromatography eluting with dichloromethane-hexanes (1:1, v/v) to give 2.7 g of the desired product.

Step F

The product from step E (2.7 g) was converted to the desired imine compound (3 g), following the similar procedure to that of Preparative Example 13.19 step D,

Step G

The imine product from step F (3 g) was dissolved in 80 mL of dichloromethane and cooled in a −78° C. bath. A solution of boron tribromide (1.0 M in dichloromethane, 9.2 mL) was added dropwise. The mixture was stirred for 4.25 h from −78° C. to 5° C. H₂O (50 mL) was added, and the layers were separated. The aqueous layer was extracted with dichloromethane. The organic layer and extracts were combined, washed with brine, and concentrated to an oily residue. The residue was dissolved in 80 mL of methanol, stirred with sodium acetate (1.5 g) and hydroxyamine hydrochloride (0.95 g) at room temperature for 2 h. The mixture was poured into an aqueous mixture of sodium hydroxide (1.0 M aq, 50 mL) and ether (100 mL). The two layers were separated. The aqueous layer was washed with ether three times. The combined ether washings were re-extracted with H₂O once. The aqueous layers were combined, washed once with dichloromethane, adjusted to pH ˜6 using 3.0 M and 0.5 M hydrogen chloride aqueous solutions, and extracted with dichloromethane. The organic extracts were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo to give 1.2 g of desired amine compound.

Preparative Example 600

Step A

Following the procedure set forth in Preparative Example 13.19 Step D, the imine was prepared from the known bromoester (1.0 g) to yield 1.1 g (79%) as a yellow solid.

Step B

The product of Step A (0.6 g) was reacted following the procedure set forth in Preparative Example 13.19 Step E to give the amine product 0.19 g (64%).

Step C

The product of Step B (1.0 g) was reacted following the procedure set forth in Preparative Example 13.19 Step B to give the acid as yellow solid 0.9 g (94%).

Step D

The product of Step C (0.35 g) was reacted following the procedure set forth in Preparative Example 13.19 Step E to give the amino acid as yellow solid 0.167 g (93%).

Preparative Example 601

Step A

To a solution of 2-methyl furan (1.72 g) in ether was added BuLi (8.38 mL) at −78° C. and stirred at room temperature for half an hour. The reaction mixture again cooled to −78° C. and quenched with cyclopropyl amide 1 and stirred for two hours at −78° C. and slowly warmed to room temperature. The reaction mixture stirred for three hours at room temperature and quenched with the addition of saturated ammonium chloride solution. The mixture was taken to a separatory funnel, washed with water, brine and dried over anhydrous sodium sulfate. Filtration and removal of solvent afforded the crude ketone, which was purified by using column chromatography to afford the ketone 3.0 g (87%) as a pale yellow oil.

Step B

To a solution of ketone (1.0 g) from Step A above in THF (5.0 mL) at 0° C. was added R-methyl oxazoborolidine (1.2 Ml, 1M in toluene) dropwise followed by addition of a solution of borane complexed with dimethyl sulfide (1.85 mL, 2M in THF). The reaction mixture was stirred for 30 minutes at 0° C. and than at room temperature for one hour. The reaction mixture was cooled to 0° C. and MeOH was added carefully. The mixture was stirred for 20 minutes and was concentrated under reduced pressure. The residue was extracted with ether, washed with water, 1M HCl (10 mL), saturated sodium bicarbonate (10.0 mL) water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and removal of solvent afforded the crude alcohol which was purified by silica gel chromatography to afford the pure alcohol 0.91 g (91%) as yellow oil.

Preparative Example 601.A

Step A

If one were to follow the procedure set forth in Preparative Example 601, but using the cyclopentylamide instead of the cyclopropylamide (prepared according to standard procedures), then one would obtain the desired alcohol.

Step B

If one were to follow the procedure set forth in Preparative Example 13.25, but instead using the alcohol from Step A above, then one would obtain the title amine.

Preparative Example 601.B

Step A

If one were to follow the procedure set forth in Preparative Example 601.A, but using 4-isopropylfuran instead of 5-methylfuran, then one would obtain the desired alcohol.

Step B

If one were to follow the procedure set forth in Preparative Example 13.25, but instead using the alcohol from Step A above, then one would obtain the title amine

Preparative Example 602

Step A

An equimolar mixture of 2-methylfuran (1.0 g) and anhydride (2.6 g) was mixed with SnCl₄ (0.05 mL) and heated at 100° C. for 3 hours. After cooling the reaction mixture, water (10 mL) was added, followed by saturated sodium carbonate solution until it becomes alkaline. The reaction mixture was extracted with ether several times and the combined ether layer was washed with water, brine and dried over anhydrous sodium sulfate. Filtration and removal of solvent afforded the crude ketone, which was purified by using silica gel chromatography to afford the ketone 0.9 g (43%) as a yellow oil.

Step B

The title alcohol was obtained following a similar procedure set forth in the Preparative Example 601.

Preparative Example 603

To a solution of 5-methyl furan-2-aldehyde (1.0 g) and 3-bromo-3,3-difluoropropene (2.24 g) in DMF (30 mL) was added indium powder (1.66 g) and lithium iodide (50.0 mg). The reaction mixture was stirred over night, diluted with water and extracted with ether. The ether layer was washed with water, brine and purified by silica gel chromatography to afford the pure alcohol 2.8 g (92%).

Preparative Examples 603A-603F

If one were to follow the procedure of Preparative Example 64, using the aldehydes, amino alcohols and organolithiums in the Table below, then the optically pure amine Products in the Table below would be obtained.

Prep. Amino Ex. Aldehyde Alcohol Organolithium Product 603A

iPrLi

603B

tBuLi

603C

tBuLi

603D

tBuLi

603E

iPrLi

603F

iPrLi

Preparative Examples 604-611

Following a similar procedure set forth in Preparative Examples 13.25 or 601 the following Alcohols were prepared.

Prep Ex Furan Electrophile Alcohol Yield 604

86% 605

69% 606

84% 607

82% 608

60% 609

65% 610

82% 611

89%

Preparative Examples 620-631

Following a similar procedure to that set forth in Preparative Example 13.25 the following Amines were prepared from the corresponding Alcohols.

Prep % Ex ALCOHOL AMINE YIELD 620

28 621

58 622

69 623

81 624

82 625

45 626

57 627

58 628

54 629

53 630

50 631

   82%

Preparative Example 1001

Step A

Oxalyl chloride (3 mL, 34.27 mmol) was added dropwise to a mixture of 2-methoxy-6-(trifluoromethyl)benzoic acid (1.5 g, 6.81 mmol) (prepared according to known method, see: EP0897904B1), N,N-dimethylformamide (0.3 mL), and dichloromethane (40 mL) with stirring at rt. The reaction mixture was stirred overnight. Evaporation of solvent and excess oxalyl chloride and drying under vacuum afforded 2-methoxy-6-(trifluoromethyl)benzoyl chloride as a solid, which was used without purification.

Step B

A solution of 2-methoxy-6-(trifluoromethyl)benzoyl chloride (ca. 6.81 mmol) from Step A above in dichloromethane (20 mL) was added dropwise to a mixture of 4-(dimethylamino)pyridine (42 mg, 0.34 mmol), triethylamine (2.8 mL, 20.09 mmol), and 2 M dimethylamine solution in tetrahydrofuran (7 mL, 14 mmol), and dichloromethane (30 mL) with stirring at rt. The reaction mixture was stirred overnight. A mixture of dichloromethane and water was added. The organic phase was separated, washed with 1N HCl solution, water, and saturated sodium bicarbonate solution and concentrated. The residue was purified by column chromatography (ethyl acetate:hexanes, 3:1 v/v) to give the product as a white solid (1.24 g, 74% over two steps).

Step C

A mixture of the amide from Step B above (1.8 g, 7.28 mmol), carbon tetrachloride (25 mL), and iron powder (305 mg, 5.46 mmol) was cooled to 0° C. Bromine (0.94 mL, 18.34 mmol) was added dropwise with stirring. After addition, the mixture was stirred at rt for 1 h and at 50° C. for 3 h. The mixture was cooled to rt, diluted with dichloromethane, and slowly poured to a cold 10% NaHSO₃ solution. After stirring at rt for 0.5 h, the organic layer was separated and concentrated to give the product as a white solid (2.26 g, 95%).

Step D

Concentrated sulfuric acid (10 mL) was added dropwise to a flask charged with the bromide from Step C above (600 mg, 1.84 mmol) at 0° C. with stirring. A mixture of nitric acid (0.2 mL, 4.76 mmol) and concentrated sulfuric acid (0.3 mL) was then added dropwise. After addition, the mixture was stirred at rt for 3 h. The mixture was added to ice-water, neutralized with 15% NaOH solution to pH 7, and extracted with dichloromethane. The organic layer was concentrated to give the product as a white solid (621 mg, 91%). mp 92° C., m/e 371 (MH⁺).

Step E

A solution of the compound from Step D above (1.2 g, 3.23 mmol) in dichloromethane (50 mL) was cooled to −75° C. 1 M BBr₃ solution in dichloromethane (7.5 mL, 7.5 mmol) was added dropwise with stirring. The mixture was stirred at −75° C. for 2 h. The mixture was added to ice-water. After stirring at rt for 0.5 h, the mixture was extracted with dichloromethane. The organic was concentrated and the residue was purified by column chromatography (dichloromethane-methanol, 9:1 v/v) to give the product as a yellow solid (1.05 g, 91%). m/e 357 (MH⁺).

Step F

A mixture of the compound from Step E above (1.08 g, 3.02 mmol), methanol (30 mL), and 10% Pd—C (250 mg) was subjected to hydrogenation at 50 psi at rt for 6 h. The mixture was filtered through a layer of Celite. The filtrate was concentrated to give the title compound as a pale yellow solid (930 mg, 96%). mp 132° C., m/e 249.

Preparative Example 1002

Step A

To a cooled (−70° C.) etherial (45 mL dry) solution of 3-bromothiophene (3.8 mL) was added BuLi (30 mL of 1.6M in hexane) dropwise, and the mixture was stirred at −70° C. for 20 min. Acetophenone (4.6 mL) in ether (6 mL) was added dropwise with stirring at −70° C. After 3 hrs, the mixture was warmed to RT and sat. NH₄Cl (aq) was added and the mixture was extracted with ether. The organic phase was dried (Na₂SO₄) and concentrated in vacuo to give the title compound which was used in Step B without further purification.

Step B

The crude product from Step A above was stirred with oxalic acid (0.375 g) at 70° C. under reduced pressure for 3 hr, then cooled to RT and extracted with ether. The organic phase was dried (Na₂SO₄) and concentrated in vacuo to give the product as a pale yellow liquid (5.7 g, 78% for Steps A-B).

Step C

To the product from Step B above (4.2 g) diluted with dichloromethane (30 mL) and containing triethylsilane (6 mL) was added TFA (3 mL) in dichloromethane (7.5 mL). After stirring at RT for 10 min, the mixture was concentrated in vacuo to give the product as a colorless liquid (4.61 g, 80%).

Step D

To an etherial (3.5 mL dry) solution of the thiophene product (1.5 g) from Step C above was added BuLi (3.2 mL of 2.5M), and the mixture was heated at reflux for 15 min, cooled to RT, and DMF (0.8 mL) in ether (3.5 mL) was added dropwise. After stirring for 30 min, sat NH₄Cl (aq) was added and the mixture was extracted with ether. The organic phase was dried (Na₂SO₄) and concentrated in vacuo to give the title compound (1.71 g, 98%).

Preparative Example 1002B

Step A

Following the procedure described in Preparative Example 1002, Step A, but using acetone instead of acetophenone, 2-thiophen-3-yl-2-propanol would be obtained.

Step B, C, D

Following the procedures described in Preparative Example 1002, steps B to D, the product from step A above would be converted to the titled 4-isopropyl-2-thiophen-aldehyde.

Preparative Example 1003

Step A

The aldehyde (0.50 g) was combined with ethylene glycol (1 mL), benzene (40 mL) and pTSA monohydrate (30 mg) and stirred at reflux for 20 hr. Cool to room temperature, add EtOAc and sat, NaHCO₃ (aq) solution, separate the organic phase, concentrate in vacuo, and purify by silica gel chromatography (EtOAc-Hex, 1:4) to give a colorless liquid (60 mg)

Step B

The product from Step A above (0.607 g) was stirred at 45° C. overnight with 1N NaOH (aq), then cooled to room temperature, acidified with 3N HCl and extracted with EtOAc. Washing with brine and concentration in vacuo gave a solid (5.0 g).

Step C

Following a similar procedure as that used in Preparative Example 1, except using the product from Step B above and dimethylamine in THF (2M), the product was obtained (1.21 g crude).

Step D

The product from Step C above was dissolved in THF and stirred with 0.3N HCl (aq) and stirred at RT for 4 hr. Concentration in vacuo gave a pale yellow oil (1.1 g, 67%).

Preparative Example 1004

Step A

To a cooled (−78° C.) solution of methoxybenzofuran-2-carboxylic acid (1 g) was added DIBAL (30 mL, 1M in THF). After stirring for 20 min, the mixture was warmed to RT and stirred for 4 hr, then poured into sat. NH₄Cl (aq) (35 mL). After stirring at RT for 20 min, 6M HCl (aq) was added and the mixture was extracted with EtOAc, the organic phase dried and then concentrated in vacuo. Purification by silica get chromatography (EtOAc-hexane, 3:7) afforded the alcohol as a solid (0.4 g, 97%).

Step B

A mixture of the product from Step A above (0.9 g), EtOAc (50 mL) and MnO2 (5.2 g) was stirred at RT for 22 h, then filtered and concentrated in vacuo. The solid was redissolved in EtOAc (50 mL), MnO2 (5.2 g) was added and the mixture was stirred for 4 additional hrs. Filtration, concentration and silica gel purification (EtOAc-Hexane, 1:3) gave the title compound as a solid (0.60 g, 67%).

Preparative Example 1004A

Step A

To a stirred solution of potassium t-butoxide (2.5 g) in HMPA (20 ml) was added 2-nitropropane (2 ml) dropwise. After 5 min, a solution of methyl-5-nitro-2-furoate (3.2 g) in HMPA (8 ml) was added to the mixture and stirred for 16 hr. Water was added and the aqueous mixture was extracted with EtOAc. The EtOAc layer was washed with water, dried with MgSO₄, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography (Hex/EtOAc, 6:1) to yield 3.6 g of product (90%).

Step B

To a solution of product from Step A (3.6 g) in toluene (16 ml) was added tributyltin hydride (5.4 ml) followed by AlBN (555 mg). The mixture was heated to 85° C. for 3.5 hr. After cooling, the mixture was separated by flash column chromatography (Hex/EtOAc, 7:1) to afford 2.06 g of product (73%).

Step C

To a solution of product from Step B (2.05 g) in THF (60 ml) at 0° C. was added a solution of LAH (1M in ether, 12.8 ml). The reaction was stirred at room temperature for 30 min. Water and 1M NaOH was added until a precipitate formed, diluted with EtOAc, stirred for 30 min and then filtered through a celite pad. The organic filtrate was concentrated in vacuo to give 1.56 g of product (93%).

Step D

To a solution of product from Step C (2.15 g) in CH₂Cl₂ (100 ml) was added Dess-Martin oxidant (7.26 g) in CH₂Cl₂ (45 ml) and stirred for 30 min. The mixture was diluted with ether (200 ml). The organic layer was washed with 1N NaOH, water and brine, dried with MgSO₄, filtered and concentrated in vacuo to give oil and solid. The material was extracted with ether and filtered. Some solid crystallized out from the filtrate, filtered again, and the filtrate was concentrated in vacuo to give 2.19 g of product.

Preparative Example 1004B

Step A

To a suspension of 5-bromo-2-furoic acid (15 g) in CH₂Cl₂ (275 ml) at room temperature was added oxalyl chloride (6.9 ml) followed by a catalytic amount of N,N′-dimethylformamide ((0.3 ml). The mixture was stirred for 1 hr, whereupon, EtOH (20 ml) and TEA (22 ml) were added and then let stir overnight. The mixture was concentrated in vacuo and extracted with hexanes and hexanes/CH₂Cl₂. The extracts were concentrated in vacuo to give an oil (17.2 g, 93%).

Step B

The product from Step A (17.2 g), aluminum trichloride (19.52 g) and carbon disulfide (150 ml) were combined in a flask. A solution of n-octadecyl bromide (24.4 g) in carbondisulfide (50 ml) was added dropwise over 45 min. The reaction was stirred for 2.5 hr, whereupon, 300 ml of crushed ice and water were added. The layers were separated and the organic layer was washed with saturated sodium bicarbonate, water, and brine. The organic layer was dried with Na₂SO₄ and concentrated in vacuo. The crude material was purified by flash column chromatography (hexanes/CH₂Cl₂, 3:1) to yield 7.91 g of product (37%).

Step C

To the product from step B (7.9 g) in THF (140 ml) at −10° C. was added a solution of LAH (1M in THF, 28.5 ml). The solution was stirred for 2.5 hrs at 15° C. Water and 1M NaOH were added carefully to the mixture, followed by EtOAc and let stir for 1.5 hr. The reaction was filtered through a silica pad and the filtrate was concentrated in vacuo to yield 6.48 g of crude product (100%).

Step D

The product from Step C (6.32 g) was dissolved in THF (140 ml) and cooled to −78° C. A solution of t-BuLi (2.5M in hexanes, 22 ml) was added dropwise and let stir for 15 min. An excess of water (70 ml) was then added and let the reaction stir another hour. CH₂Cl₂ (300 ml) and brine (50 ml) were added and the layers were separated. The organic layer was dried with Na₂SO₄ and concentrated in vacuo to give 5.33 g of crude product.

Step E

To a solution of the product from Step D (5.33 g) in CH₂Cl₂ (100 ml) was added a solution of Dess-Martin periodinane in CH₂Cl₂ (15 wt %, 12.6 g). The mixture was stirred for 1.5 hr and then diluted with ether (400 ml) and washed with 1N NaOH, water and brine. The organic layer was dried with Na₂SO₄ and filtered through a magnesium sulfate/silica pad. The filtrate was concentrated in vacuo and purified via flash column chromatography (hex/EtOAc, 50:1, 25:1) to yield 3.06 g of an oil (74%).

Preparative Example 1005

Following a similar procedure as that described in Preparative Example 1004, except using 5-chlorobenzofuran-2-carboxylic acid (1.5 g), the title compound was obtained (solid, 0.31 g, 24%).

Preparative Example 1006

Step A

The sulfonyl chloride from Preparative Example 13.29 Step A (1.5 g) was stirred with AlCl3 and benzene for 15 min at 20° C. Treatment with NaOH, extraction with Et₂O, concentration in vacuo, and purification by column chromatography (silica, hexane-EtOAc, 5:2) gave the phenylsulfone (1.5 g, 84%, MH⁺=255).

Step B

Following similar procedures as those used in Preparative Example 13.29 Steps C-G, except using the sulfone from Step A above, the title compound was prepared (0.04 g, 27%, MH⁺=256).

Preparative Example 1030

The product of Preparative Example 34.18 Step B (2 g, 8 mmol) was stirred with morpholine (0.9 mL, 10.29 mmol) and K₂CO₃ (2.2 g, 15.9 mmol) in 50 mL of acetone at RT to obtain the morpholinobutylfuran derivative (1.22 g, 73%).

Step B

Following a similar procedure as that in Preparative Example 34.18 Step D, but using the product (1.2) from Step A above, the title aldehyde was prepared (0.9 g, 66%, 1:0.7 regioisomeric mixture).

Preparative Example 1030-A

Following a similar procedure as that in Preparative Example 1030 Steps A-B, but using N-methylpiperazine instead of morpholine, the title aldehyde could be prepared.

Preparative Example 1030-B

Following a similar procedure as in Preparative Example 1030 Steps A-B, but using N,N-dimethylamine instead of morpholine, the title aldehyde could be prepared.

Preparative Example 1031

A solution of 5-bromobenzofuran (950 mg, 4.82 mmol) in anhydrous ether (12 mL) was cooled to −78° C. 1.7 M tert-BuLi solution in pentane (6 ml, 10.2 mmol) was added dropwise under argon. After addition, the mixture was stirred at −78° C. for 20 min, followed by addition of a mixture of DMF (0.8 mL) and ether (1 mL). The mixture was allowed to warm to rt and stirred for 0.5 h. Ethyl acetate was added. The mixture was poured to saturated ammonium chloride solution. The organic layer was separated and concentrated. The residue was purified by column chromatography (ethyl acetate-hexanes, 1:5 v/v) to give the title compound as a pale yellow solid (490 mg, 70%).

Preparative Examples 1040-1054

Following the procedure set forth in Preparative Example 64 but using the commercially available (or prepared) aldehyde, aminoalcohols, and organolithium reagents in the Table below, the optically pure amine products in the Table below were obtained.

Prep. Amino Organo- 1. Yield (%) Ex. Aldehyde Alcohol lithium Product 2. (M + 1)⁺ 1040

EtLi

1. 24% 2. 267 1041

EtLi

1. 94% 2. 176 (m/e) 1042

EtLi

1. 67% 2. 229 (M-16) 1043

i-PrLi

1. 60% 2. 151 [M-16] 1044

EtLi

1. 74% 2. 194 (M-16) 1045

EtLi

1. 33% 2. 165 [M-NH2]⁺ 1046

EtLi

1. 31 2. 179 [M-NH2]⁺ 1047

t-BuLi

1. 31% 2. 188 1048

t-BuLi

1. 10% 2. 154 1049

EtLi

1. 73% 2. 137 [M-NH2]⁺ 1051

t-BuLi

1. 17% 1054

t-BuLi

1. 79% 2. 151 (M-16)

Preparative Examples 1100-1126

Following the procedure set forth in Preparative Example 34 but using the commercially available aldehydes and Grignard/Organolithium reagents listed in the Table below, the amine products were obtained.

Prep. Organo-metallic 1. Yield (%) Ex. Aldehyde Reagent Product 2. (M + 1)⁺ 1100

t-BuLi

1. 83% 2. 190 (M-16) 1101

t-BuLi

1. 46% 2. 204 1102

t-BuLi

1. 48% 2. 194 1103

t-BuLi

1. 51% 2. 194 1104

t-BuLi

1. 12% 2. 238 1105

t-BuLi

1. 39% 2. 234 1106

t-BuLi

1. 44% 2. 194 (m/e) 1107

t-BuLi

1. 57% 2. 150 (M-16) 1108

t-BuLi

1. 31% 2. 224 1109

t-BuLi

1. 11% 2. 224 1110

t-BuLi

1. 57% 2. 224 1111

t-BuLi

1. 21% 2. 224 1112

c-Pentyl-Li

1. 58% 2. 190 1113

t-BuLi

1. 20% 2. 248 1114

t-BuLi

1. 24% 2. 232 1115

EtLi

1. 32% 2. 177 (M-NH2) 1116

t-BuLi

1. 26% 2. 205 (M-NH2) 1117

t-BuLi

1. 50% 2. 190 (M-NH2) 1118

t-BuLi

1. 29% 2. 200 1119

t-BuLi

1. 28% 2. 232 1120

t-BuLi

1. 76% 2. 224 1121

t-BuLi

1. 40% 2. 206 1122

t-BuLi

1. 38% 2. 236 1123

t-BuLi

1. 70% 2. 192 1124

t-BuLi

1. 81% 2. 204 1125

t-BuLi

33% 1126

t-BuLi

50%

Preparative Examples 1200A-1204A

Following the procedure set forth in Preparative Example 13.29 but using the commercially available amines, the hydroxyaminothiophene products listed in the Table below were obtained.

Prep. 1. Yield (%) Ex. Amine Product 2. (M + 1)⁺ 1200A

1. 3% 2. 342 1201A

1. 41% 2. 265 1202A

1. 17% 2. 237 1203A

1. 1% 1204A

1. 15% 2. 375.1

Preparative Example 1205A

Step A

Dibenzylsulfonamide-thiophene-amine (660 mg, 1.76 mmol), available from Preparative Example 1204A, was stirred with 4 mL of concentrated sulfuric acid at room temperature for 5 h. Ice water (50 mL) was added. The aqueous mixture was adjusted to pH ˜5 using a 1.0 M NaOH aqueous solution, and extracted with ethyl acetate (200 mL×4). The organic extracts were washed with H₂O and brine, dried over MgSO₄, filtered, and concentrated in vacuo to yield 237 mg of the desired sulfonamide amine (69%, MH⁺=194.23, [M−NH₂]⁺=178).

Preparative Examples 1300

The title compound from Preparative Example 13.32 (0.35 g) was treated with concentrated sulfuric acid (3 mL) for 6 hrs, then poured on ice, and the pH adjusted to 4 with NaOH. Extraction with EtOAc, and drying of the organic phase over Na₂SO₄ gave the title compound (159 mg, 64%, MH⁺=223).

Preparative Examples 1301

Step A

Following the procedure set forth in Preparative Example 605 but using the commercially available fluoroisopropylester, the alcohol product was obtained (1.2 g, 84%, M−OH=155).

Step B

Following the procedure set forth in Preparative Example 625 but using the alcohol from Step A above, the amine product was obtained (350 mg, 35%, M−NH2=155).

Preparative Examples 1302

Step A

Following a similar procedure as that used in Preparative Example 13.29 Step B, except using the commercially available arylsulfonylchloride (0.15 g) and diethylamine (2.2 eq), the dimethylsulfonamide was obtained (0.12 g, 71%, MH⁺=323).

Step B

Following a similar procedure as that used in Preparative Example 13.29 Step C, except using the product from Step A above (0.12 g), the phenol was obtained (0.112 g, 98%).

Step C

Following a similar procedure as that used in Preparative Example 10.55 Step C, except using the product from Step B above (0.112 g), the title compound was obtained (0.1 g, 99%, MH⁺=245).

Preparative Examples 1303

Following a similar procedure as that used in Preparative Example 1302 Steps A-C, except using piperidine in Step A (0.078 g) instead of diethylamine, the title compound was obtained (0.070 g, 35%, MH⁺=257).

Preparative Examples 1304

Following a similar procedure as that used in Preparative Example 1302 Steps A-C, except using dimethylamine (2M in THF) in Step A instead of diethylamine, the title compound was obtained (1.92 g, 72%, MH⁺=217).

Preparative Examples 1304A

Following a similar procedure as that used in Preparative Example 1302 Steps A-C, except using morpholine in Step A instead of diethylamine, the title compound could be obtained.

Preparative Examples 1304B

Following a similar procedure as that used in Preparative Example 1302 Steps A-C, except using N-methylamine in Step A instead of diethylamine, the title compound could be obtained.

Preparative Examples 1305

Step A

Following a similar procedure as that used in Preparative Example 1302 Step A, except using the phenethylamine indicated (4.99 g), the product was obtained (5.96 g, 86%, MH⁺=210).

Step B

The compound from Step A above (5.0 g) was added to 30 g of PPA at 150° C. and the resulting mixture stirred for 20 min, before being poured on ice and extracted with dichloromethane. The organic phase was dried over MgSO4 concentrated in vacuo and purified by silica gel chromatography (EtOAc:MeOH, 95.5) to give the product (0.5 g, 9%).

Step C

Following a similar procedure as that used in Preparative Example 13.3 Step D, except using the compound from Step B above (0.14 g), the product was obtained (0.18 g, 87%, MH⁺=256)

Step D

Following a similar procedure as that used in Preparative Example 11 Step B, except using the compound from Step C above (0.18 g), the product was obtained (0.17 g).

Step E

Following a similar procedure as that used in Preparative Example 13.3 Step B, except using the compound from Step D above (0.17 g), the product was obtained (0.17 g, 95%, MH⁺=315).

Step F

Following a similar procedure as that used in Preparative Example 13.29 Step C, except using the product from Step E above (0.17 g), the nitrophenol was obtained (0.165 g, 99%, MH⁺=303).

Step G

Following a similar procedure as that used in Preparative Example 10.55 Step C, except using the product from Step F above (0.165 g), the title compound was obtained (0.128 g, 86%, MH⁺=193).

Preparative Examples 1306

Step A

Following a similar procedure as that used in Preparative Example 11 Step B, except using the lactam (0.179 g), the title compound was obtained (0.25 g, 25%).

Step B

Following a similar procedure as that used in Preparative Example 13.29 Step C, except using the product from Step A above (0.055 g), the phenol was obtained (0.045 g, 99%).

Step C

Following a similar procedure as that used in Preparative Example 10.55 Step C, except using the product from Step B above (0.045 g), the title compound was obtained (0.022 g, 57%, MH⁺=179).

Preparative Examples 1307

Following a similar procedure as that used in Preparative Example 2, except using 3(R)-hydroxypyrrolidine HCl (1.36 g), the title compound was obtained (2.25 g, 89%).

Preparative Examples 1308

Following a similar procedure as that used in Preparative Example 2, except using morpholine, the title compound was obtained (3.79 g).

Preparative Examples 1309

Step A

Following a similar procedure as that used in Preparative Example 13.29 Step B, except using the commercially available nitrophenylsulfonylchloride and diethylamine (2.2 eq), the dimethylsulfonamide was obtained (90%, MH⁺=231).

Step B

Following a similar procedure as that used in Preparative Example 10.55 Step C, except using the product from Step B above, the title compound was obtained (45%, MH⁺=201).

Preparative Examples 1310

Step A

Following a similar procedure as that used in Preparative Example 13.29 Step B, except using the commercially available nitrobenzoylchloide and the commercially available amine indicated, the benzamide was obtained (13%, MH⁺=253).

Step B

Following a similar procedure as that used in Preparative Example 10.55 Step C, except using the product from Step B above, the title compound was obtained (94%, MH⁺=223).

Preparative Examples 1310A

Step A

Following a similar procedure as that used in Preparative Example 13.29 Step B, except using the commercially available nitrobenzoylchloride and dimethylamine, the benzamide could be obtained.

Preparative Examples 1311

Step A

To a benzene (20 mL) solution of methoxythiophenesulfonylchloride (1.5 g) was added AlCl₃ (2.0 g) at RT. After 15 min, the mixture was added to 0.1N HCl (aq) with stirring, then extracted with Et₂O. Washing the organic phase with bring, drying over MgSO₄, concentration in vacuo and purification by silica gel chromatography (Hexane:EtOAc, 5:2) gave the title compound (1.5 g, 84%).

Step B

Following a similar procedure as that used in Preparative Example 13.29 Steps C-G, except using the product from Step A above, the title compound was obtained (3%, MH⁺=380).

Preparative Examples 1312

Step A

Following a similar procedure as that used in Preparative Example 1311 Step A, except using the commercially available sulfonylchloride, the diphenylsulfone was obtained (880 mg, 80%).

Step B

Following a similar procedure as that used in Preparative Example 11 Step B, except using the product from Step A above, the title compound was obtained (0.90 g, 97%),

Step C

Following a similar procedure as that used in Preparative Example 10.55 Step C, except using the product from Step B above (0.16 g), the title compound was obtained (0.106 g, 95%).

Preparative Examples 1313

Step A

Following a similar procedure as that used in Preparative Example 1311 Step A, except using the commercially available phenol (2 g), the nitroacid was obtained (˜13 mmol).

Step B

Oxallyl chloride (3.5 mL) and two drops of DMF was added to the product from Step A above (˜13 mmol) dissolved in dichloromethane (100 mL). After stirring at RT overnight, the mixture was concentrated in vacuo, diluted with dichloromethane (50 mL), cooled to 0° C. Dimethylamine in THF (20 mL of 2N) and TEA (8 mL) were added. After 3 hr of stirring, the mixture was concentrated in vacuo, aq NaOH (1M) was added, and the mixture was extracted with dichloromethane. The pH of the aq layer was adjusted to pH=2 using 6N HCl (aq), and extracted with dichloromethane. The combined organic extracts were washed with brine, dried, concentrated in vacuo, and the product purified by silica gel chromatography (700 mL dichloromethane/20 mL MeOH/1 mL AcOH) to give the title compound (800 mg, 27% for two steps).

Step C

Following a similar procedure as that used in Preparative Example 10.55 Step C, except using the product from Step B above (780 mg), the title compound was obtained (0.46 g, 68%).

Preparative Examples 1313A

By following a similar procedure as that used in Preparative Example 1001, steps C, D, E and F, using the known 2-ethyl-6-methoxy-N,N-dimethyl-benzamide (WO 9105781, 2.1 g), the amine was obtained (53%, 1.1 g, MH⁺=209.1).

Preparative Examples 1313B

Step A

The benzamide (0.70 g, 3.125 mmol) was dissolved in dry ether (10 ml) under argon and cooled to −78 C. t-butyl lithium (4.2 mL, as 1.7M solution in pentane) was added. The mixture was stirred at −78° C. for 1.5 hr. 2-Iodopropane (7.8 mmol) was added and the mixture warmed to room temperature and stirred for an additional 16 hrs. Water was added to quench, and the mixture was washed with water, then with 1N HCl. The organic phase was dried (Na2SO4) and concentrated. Flash column chromatography (10:1 Hexane-EtOAc) provided the t-butyl compound (33 mg, 4%, MH+=280.9).

Step B

A solution of the compound 1004 (1.2 g, 3.23 mmol) in dichloromethane (50 mL) was cooled to −75° C. 1M BBr₃ solution in dichloromethane (7.5 mL, 7.5 mmol) was added dropwise with stirring. The mixture was stirred at −75° C. for 2 h. The mixture was added to ice-water. After stirring at rt for 0.5 h, the mixture was extracted with dichloromethane. The organic was concentrated and the residue was purified by column chromatography (dichloromethane-methanol, 9:1 v/v) to give the product 1005 as a yellow solid (1.05 g, 91%). m/e 357 (MH⁺), ¹H NMR (CDCl₃) δ 8.44 (s, 1H), 3.12 (s, 3H), 2.87 (s, 3H).

Preparative Example 1314

Step A

Methyl-4-bromo-3-hydroxy-2-thiophenecarboxylate (20 g, 84.36 mmol) was dissolved in 400 mL of acetone. Potassium carbonate (58 g, 420.3 mmol) was added followed by iodomethane (45 mL, 424 mmol). The resulting mixture was heated at reflux for 4.5 h. After cooling, the mixture was filtered through a thin Celite pad, rinsing with methylene chloride. The filtrate was concentrated in vacuo to give 22.5 g to of methyl-4-bromo-3-methoxy-2-thiophenecarboxylate (crude, 100%, MH⁺=251.0) as a dark green solid.

Step B

The product from Step A above (22.5 g, 84.36 mmol) was dissolved in 60 mL of tetrahydrofuran and added with 125 mL of a 1.0 M NaOH aqueous solution. The mixture was stirred at room temperature for 4 d, then washed with ether (60 mL×2), acidified to pH ˜2 using a 1.0 M HCl aqueous solution. Solids were precipitated out after acidification, and collected by filtration. The solid was dissolved in methylene chloride-ethyl acetate (˜4:1, v/v). The organic solution was washed with H₂O and brine, dried with Na₂SO₄, and concentrated in vacuo to a light yellow solid, further dried on height vacuum, yielding 17.95 g of 4-bromo-3-methoxy-2-thiophene carboxylic acid (90%, MH⁺=237.0).

Step C

The carboxylic acid (3.26 g, 13.75 mmol) available from Step B above was treated with 30 mL of concentrated sulfuric acid. The mixture was sealed in a one-neck round bottom flask, and heated at 65° C. for 4.5 h. After cooled to room temperature, the mixture was poured into 200 mL of crushed ice, and extracted with methylene chloride (100 mL×3). The organic extracts were combined, washed successively with H₂O (50 mL×2), sat. NaHCO₃ (50 mL×3), and brine (50 mL). The organic solution was dried with Na₂SO₄, and concentrated in vacuo to a dark brown oil, which was purified by flash column chromatography (biotage, SiO₂ column) using hexanes-methylene chloride (3:1, v/v) as eluents. Removal of solvents afforded 1.83 g of 3-bromo-4-methoxy thiophene (69%) as a light yellow oil.

Step D

To a stirred solution of 3-bromo-4-methoxythiophene (550 mg, 2.85 mmol), prepared in Step C above, in 30 mL of methylene chloride at −78° C. was added dropwise along the inside wall of the flask chlorosulfonic acid (0.48 mL, 7.21 mmol). The mixture was stirred at −78° C. for 10 nm, continued at room temperature for 1 h, and filtered through a 1-in silica gel pad, rinsing with methylene chloride. The filtrate was concentrated in vacuo to give 270 mg of 4-bromo-3-methoxy-2-thiophene sulfonylchloride (33%) as a light yellow oil.

Step E

To a stirred solution of thiophene sulfonylchloride (270 mg, 0.926 mmol) prepared in Step D above in 15 mL of methylene chloride at room temperature was added triethylamine followed by N-methyl-tertbutylamine (0.25 mL, 2.094 mmol). After 20 h, the mixture was diluted with 50 mL of methylene chloride, and washed with H₂O and brine. The organic solution was dried over Na₂SO₄, filtered, and concentrated to an oily residue, which was purified by preparative TLC (methylene chloride as eluent) to afford 73 mg of the titled bromo-sulfonamide (23%) as a near colorless oil.

Step F

A one-neck round bottom flask was charged with bromo-sulfonamide (73 mg. 0.2133 mmol, from Step E above), palladium acetate (5 mg, 0.0223 mmol), binap (0.03212 mmol), cesium carbonate (139 mg, 0.4266 mmol), and benzophenonimine (0.06 mL, 0.358 mmol). The mixture was evacuated via house vacuum, and refilled with nitrogen. A 3 mL of anhydrous toluene was added. The mixture was evacuated again, refilled with nitrogen, and heated at reflux for 2.5 d. After cooled to room temperature, methylene chloride (50 mL) was added, the mixture was filtered through a Celite pad, rinsing with methylene chloride. The filtrated was concentrated in vacuo to give 205 mg (crude, MH⁺=443.1) of the desired imine product as a dark brown oil, used in next step without purification.

Step G

The imine from Step F above (205 mg, crude, 0.2133 mmol) was dissolved in 5 mL of methanol, and added with sodium acetate (81 mg, 0.9873 mmol) followed by hydroxylamine hydrochloride (68 mg, 0.98 mmol). The mixture was stirred at room temperature for 6.5 h, quenched with the addition of 10 mL of a 1.0 M NaOH aqueous solution. The aqueous mixture was extracted with methylene chloride (30 mL×3). The extracts were combined, washed with brine, dried by Na₂SO₄, and concentrated in vacuo to a dark yellow oil, which was purified by preparative TLC (methylene chloride-methanol=100:1, v/v) to give 34 mg (57% over two steps, MH⁺=279.0) of methoxy-thiophenesulfonamide amine as a light yellow oil, solidified on standing.

Step H

To a stirred suspension of sodium hydride (60%, 45 mg, 1.13 mmol) in 3 mL of anhydrous N,N′-dimethylformamide (DMF) was added dropwise ethanethiol (0.1 mL, 1.34 mmol). After 10 min, the mixture turned into a clear solution, and 1 mL of this solution was taken up in a syringe and added dropwise to a stirred solution of methoxy-thiophenesulfonamide amine in 1 mL of DMF. The mixture was heated up to 95° C., and continued for 3.5 h. After cooling, the mixture was poured into 20 mL of a 1.0 M NaOH aqueous solution. The aqueous mixture was washed with methylene chloride (30 mL×3). The organic washings were combined, re-extracted with a 1.0 M NaOH aqueous solution (15 mL) and H₂O (15 mL). The aqueous layer and aqueous extracts were combined, adjusted to pH ˜6 using a 1.0 M HCl aqueous solution, and extracted with methylene chloride (75 mL×3). The organic extracts were washed with brine, dried (Na₂SO₄), and concentrated in vacuo to a dark yellow oil. This oil was dissolved in ethyl acetate (50 mL), washed with H₂O (10 mL×2) and brine (10 mL). The organic solution was dried (Na₂SO₄), and concentrated in vacuo to afford 36 mg (100%, MH⁺=265.0) of hydroxyl-thiophene sulfonamide amine as a yellow oil.

Preparative Example 1315

Step A

Following the procedures described in Preparative Example 1314 Step E, 4-bromo-3-methoxy-2-thiophene-sulfonyl chloride (190 mg, 0.65 mmol, available from Step D, Preparative Example 1314) was converted to the titled tert-butyl sulfonamide (56 mg, 26%, MH⁺=328.1) upon treatment of triethylamine (0.28 mL, 2.0 mmol) and tert-butylamine (0.15 mL, 1.43 mmol) in 10 mL of methylene chloride.

Step B

tert-Butyl sulfonamide (98 mg, 0.3 mmol) available from Step A above was converted to the imine product (296 mg, crude, MH⁺=429.1) by using the procedure described in Step F of Preparative Example 1314.

Step C

The imine product (296 mg, crude, ˜0.3 mmol) was transformed to the desired thiophene-amine (23 mg, 30% over two steps, MH⁺=265.0) by using the procedure described in Step G of Preparative Example 1314.

Step D

If one were to apply the procedure set forth in Step H of Preparative Example 1314, but using the thiophene amine available from Step C above, one would obtain the titled hydroxyl thiophene sulfonamide amine,

Preparative Example 1316

Step A

Following the procedures set forth in Preparative example 13.29 Step B through F, but using diethylamine, 3-methoxy-2-thiophenesulfonyl chloride (available from Step A, Preparative example 13.29) was converted to titled diethylsulfonamido thiophene imine (MH⁺=429.1)

Step B

Thiophene-imine (1.5 g, 3.5 mmol), available from Step A above, was dissolved in 30 mL of CH₂Cl₂, and added with potassium carbonate (1.2 g, 8.70 mmol) followed by drop wise addition of bromine (0.32 mL, 6.25 mmol). After stirred for 2 d, H₂O was added. The two layers were separated. The aqueous layer was extracted with CH₂Cl₂ (50 mL×2). The organic layers were combined, washed with a 10% Na₂S₂O₃ aqueous solution (40 mL×2) and brine (40 mL), dried over Na₂SO₄, and concentrated in vacuo to a dark brown oil. This oil was separated by preparative TLC (CH₂Cl₂ as eluent), to give 0.96 g (54%) of the desired bromo-imine as a bright yellow oil (M⁺=507, M+2=509)

Step C

Bromo-imine (0.95 g, 1.87 mmol), available from Step B above, was dissolved in 15 mL of anhydrous THF, cooled in a −78° C. bath, and treated with a 2.5 M solution of n-butyl lithium in hexanes (1.2 mL, 3.0 mmol) drop wise along the side wall of the flask. After 30 min, Iodomethane (0.35 mL, 5.62 mmol) was added drop wise. Reaction was continued for 5 h, during which time the cooling bath was allowed to warm slowly to 0° C. The mixture was quenched by H₂O (25 mL), and extracted with CH₂Cl₂ (50 mL×2). The organic extracts were washed with brine, dried with Na₂SO₄, and concentrated in vacuo to give 0.93 g (crude, >100%) of the desired methylated imine as a dark yellow oil (MH⁺=443.1)

Step D

The crude methyl-imine (0.93 g), prepared in step C above, was converted to the methyl-hydroxyl-amine (0.21 g, 41%, MH⁺=265.0) by using the procedures described in Step G of Preparative Example 13.29.

Preparative Example 1316A

Step A

Following the procedures described in Preparative Example 1314 Step E, but using cycloproyl amine, the titled cyclopropyl-sulfonamide was prepared from 4-bromo-3-methoxy-2-thiophene-sulfonylchloride (available from Step D, Preparative Example 1314).

Step B

Cyclopropyl-sulfonamide, available from Step A above, was treated with potassium carbonate and iodomethane in reflux acetone to afford N-methyl-N-cyclopropyl sulfonamide.

Step C, D, E

Following the procedures set forth in Preparative Example 1314, steps F to H, N-methyl-N-cyclopropyl sulfonamide from Step B above was converted to the hydroxyl-amino-thiophene sulfonamide (MH⁺=249.0)

Preparative Example 1317-1318

Following the procedures set forth in Preparative Example 1314 but using the commercially available amines, the hydroxyaminothiophene products listed in the Table below could be prepared.

Prep. Ex. Amine Product 1317

1318

Preparative Example 2000

The thiadiazoleoxide from Preparative Example 22.1 (55 mg, 0.17 mmol) was added to R-2-phenylpropylamine (0.024 mL, 0.17 mmol) in methanol (2 ml) with diiospropylethylamine (100 μL). The reaction mixture was microwaved at 100 W for 4 hr then purified by preparative HPLC. Concentration of desired fractions gave the pure product (12.4 mg, 18%). MH⁺=413.9.

Preparative Example 2001

The thiadiazoleoxide from Preparative Example 22.2 (56 mg, 0.2 mmol) was added to 2-amino-6-cyanophenol (27 mg, 0.2 mmol) in methanol (2 ml) with diiospropylethylamine (100 μL). The reaction mixture was microwaved at 100 W for 24 hr then purified by preparative HPLC. Concentration of desired fractions gave the pure product (1 mg, 15%). MH⁺=367.9.

Preparative Example 2001A

To a solution of the Thiadiazole mono-oxide intermediate from Preparative Example 22.1 (100 mg, 0.3086 mmol) and the Furyl amine from Preparative Example 75.1 (43 mg, 0.3086 mmol) in methanol (2 mL) was added sodium trifluoro acetate (84 mg, 0.6172 mmol), followed by drop wise addition of diisopropylethylamine (80 mg, 0.6172 mmol). The reaction mixture was stirred over night at room temperature, solvents were removed under reduced pressure and the product was purified by preparative thin layer chromatography using Dichloromethane-Methanol (20:1) to afford the compound as a white solid. (Yield: 98 mg, 74%, m.p=140° C.)

Preparative Examples 2001.2-2001.55

Following a similar procedure to that set forth in Preparative Example 2000, but using the amine and the thiadiazoleoxide intermediate from the Preparative Example indicated in the Table below, the thiadiazoleoxide products in the Table below were prepared. “Comm. Available” stands for “Commercially Available”.

Prep Ex of Thiadiazole 1. Yield oxide Prep Ex 2. mp (° C.) Ex. Intermediate of Amine Product 3. MH⁺ 2001.2 22.1 74  

1. 15% 3. 442 2001.3 22.1 75.45

used crude 2001.4 22.1 75.1 

1. 62% 3. 417.9 2001.5 22.1 75.9 

1. 9% 2. 110 3. 446 2001.6 22.1 75.44

1. 11% 3. 446 2001.7 22.1 75.49

1. 6% 2. 107 3. 418 2001.8 23.1 75.1 

1. 32% 3. 386 2001.9 23.9 64.1 

1. 32% 2. 156 3. 440 2001.10 23.9 64.2 

used crude 2001.11 23.9 75.1 

used crude 2001.12 22.1 64.4 

1. 50% 2. 171 3. 380 2001.13 22.1 64.3 

1. 49% 2. 171 3. 380 2001.14 22.1 51.26

used crude 2001.15 22.2 1308   

1. 28% 3. 456.1 2001.16 22.1 13.18

used crude 2001.17 22.1 75.60

used crude 2001.18 22.1 64.5 

used crude 2001.19 22.1 75.29

used crude 2001.20 22.1 72  

used crude 2001.21 22.1 75.34

used crude 2001.22 22.1 75.62

used crude 2001.23 22.1 75.92

1. 25% 2. 102 3. 482 2001.24 23.3 75.1 

1. 9% 2. 145 3. 460 2001.25 23.1 75.61

1. 24% 3. 514 2001.26 23.1 64.1 

1. 42% 3. 482 2001.27 22.1 75.61

1. 37% 2. 172 3. 446 2001.28 22.2 2 

1. 49% 3. 456 2001.29 22.2 145   

1. 50% 2. 469 2001.30 22.1 75.63

1. 9% 3. 454 2001.31 22.2 1307   

1. 42% 3. 456 2001.32 22.1 623   

1. 31% 2. 60 3. 444 2001.33 22.1 64.12

1. 6% 3. 400 2001.34 22.1 75.27

1. 11% 3. 457.9 2001.35 22.1 64.6 

1. 25% 3. 366 2001.36 23.8 64.1 

1. 7% 3. 491.9 2001.39 22.1 75.19

used crude 2001.40 22.1 75.38

1. 37% 2. 149 3. 432.1 2001.41 23.9 75.29

1. 71% 2. 90 3. 512.1 2001.42 22.1 75.68

1. 63 2. 152 3. 390.1 2001.43 22.1 75.31

1. 59% 2. 150 3. 446 2001.44 23.9 75.64

1. 42% 2. 178 3. 494.1 2001.45 23.9 75.1 

1. 48% 2. 182 3. 480.1 2001.46 22.1 comm. available

1. 82% 2. 80 3. 394.1 2001.47 22.1 comm. available

1. 87 2. 80 3. 394.1 2001.48 22.1 75.64

1. 32% 2. 149 3. 432.1 2001.49 22.1 13.25

1. 70% 2. 110 3. 486.1 2001.50 22.1 51.22

1. 53% 2. 188 3. 500.1 2001.51 22.1 51.21

1. 10% 2. 120 3. 478.1 2001.52 23.10 75.1 

used crude 2001.53 22.1 13.11

used crude 2001.54 23.3 75.64

used crude 2001.55 22.1 75.92

1. 25% 2. 102 3. 482

Preparative Examples 2203-2245

If one were to follow a procedure similar to that set forth in Preparative Example 2001A, but using the commercially available (or prepared amine) and the thiadiazoleoxide intermediate from the Preparative Example(s) indicated in the Table below and stirring the reaction mixtures at room temperature up to reflux, the thiadiazoleoxide products in the Table below could be obtained.

Prep Ex of Thiadiazole Prep oxide Ex. Intermediate Amine Product 2203 22.1

2206 22.1

2207 22.1

2208 22.3

2209 22.3

2210 22.3

2211 22.3

2212 22.3

2213 22.3

2214 22.4

2215 22.4

2216 22.4

2217 22.4

2218 22.4

2219 22.4

2220 22.5

2221 22.5

2222 22.5

2223 22.5

2224 22.5

2225 22.5

2226 22.6

2227 22.6

2228 22.6

2229 22.6

2230 22.6

2231 22.6

2232 22.7

2233 22.7

2234 22.7

2235 22.7

2236 22.7

2237 22.7

2238 22.1

2239 22.1

2240 22.3

2241 22.3

2242 22.4

2243 22.4

2244 22.5

2245 22.5

2246 22.6

2247 22.6

2248 22.7

2249 22.7

2250 22.25 75.44

2251A 22.23 74  

2251B 22.23 75.44

2251C 22.24 74  

Preparative Examples 2252-2373

If one were to follow a procedure similar to that set forth in Preparative Example 2201A, but using the amines from the Preparative Examples indicated in the Table below (or the commercially available amines indicated in the Table below), and the thiadiazoleoxide intermediates from the Preparative Examples indicated in the Table below and stirring the reaction mixtures at room temperature up to reflux, the thiadiazoleoxide products in the Table below could be obtained.

Prep. Ex. (Thiadiazole Prep. Prep oxide Ex. Ex. Intermediate) (Amine) Product 2252 22.24  75.44

2254 22.26  75.44

2255 22.1

2256 22.1

2257 22.1  75.66

2258 22.1  75.30

2259 22.1  75.50

2260 22.1 603D

2262 22.1  75.10

2263 22.1  75.10E

2264 22.29  75.44

2265 22.39 603C

2266 22.30  75.44

2267 22.6  75.1

2268 22.6  75.9

2269 22.39  75.44

2270 22.6  75.61

2271 23.9  75.44

2272 22.27  75.44

2273 22.28  75.10

2274 22.28  75.61

2275 22.31  75.44

2276 22.32  75.61

2277 22.32  75.10

2278 22.32  75.44

2279 22.32  75.9

2280 22.32  75.60

2281 22.32  75.30

2282 22.32  75.52

2283 22.47  75.60

2284 22.34  75.52

2285 22.48  75.44

2286 22.1  75.67

2287 22.36  75.44

2289 22.41  75.44

2291 22.32  75.201

2292 22.32  75.200

2293 22.47  75.201

2294 22.47  75.200

2295 22.4  75.201

2296 22.4  75.200

2297 22.45  75.201

2298 22.45  75.200

2299 22.46  75.201

2300 22.46  75.200

2301 22.39  75.201

2302 22.39  75.200

2303 22.39 601.A

2304 22.39 601.B

2305 22.1  75.93

2306 22.1  64.11

2307 22.48  75.1

2308 22.37  75.9

2309 22.50  51.26

2310 22.51  75.9

2311 22.16  75.1

2312 22.51  51.26

2313 22.38  75.1

2314 22.7  75.61

2315 22.7  75.10

2316 22.7  75.10E

2317 22.7 603A

2318 22.7 603B

2319 22.7 603C

2320 22.19  75.10

2321 22.19  75.10E

2322 22.19 603A

2323 22.19 603B

2324 22.19 603C

2325 22.20  75.10

2326 22.20  75.10E

2327 22.20 603A

2328 22.20 603B

2329 22.20 603C

2330 22.21  75.10

2331 22.21  75.10E

2332 22.21  75.10E

2333 22.21 603A

2334 22.21 603B

2335 22.21 603C

2336 22.19  75.61

2337 22.20  75.61

2338 22.21  75.61

2339 22.22  75.61

2340 22.22  75.10

2341 22.22  75.10E

2342 22.22 603A

2343 22.22 603B

2344 22.22 603C

Preparative Examples 2400-3087

If one were to tallow a procedure similar to that set forth in Preparative Example 2201A, but using the amines from the Preparative Examples indicated in the Table below (or the commercially available amines indicated in the Table below), and the thiadizoleoxide intermediates from the Preparative Examples indicated in the Table below and stirring the reaction mixtures at room temperature up to reflux, the thiadiazoleoxide products in the Table below could be obtained.

Prep Prep Prep Ex Ex. Ex (Amine) Product 2401 160  75.20

2402 160 2-Bromo- PhNH2

2403 160 2,3- Dichloro- PhNH2

2404 161  75.49

2405 161  75.9 

2406 161  75.44

2408 161  75.20

2409 161 PhNH2

2410 161 2-Bromo- PhNH2

2411 161 2,3- Dichloro- PhNH2

2412 161  74

2413 161  75.60

2414 162  75.61

2415 162  75.49

2416 162  75.9

2417 162  75.44

2418 162  75.61

2419 162  75.20

2420 162 PhNH2

2421 162 2-Bromo- PhNH2

2422 162 2,3- Dichloro- PhNH2

2423 162  74

2424 162  75.60

2425 163  75.1

2426 163  75.49

2427 163  75.9

2428 163  75.44

2429 163  75.61

2430 163  75.20

2431 163 PhNH2

2432 163 2-Bromo- PhNH2

2433 163 2,3- Dichloro- PhNH2

2434 163  74

2435 163  75.60

2436 164  75.1

2437 164  75.49

2438 164  75.9

2439 164  75.44

2440 164  75.61

2441 164  75.20

2442 164 PhNH2

2443 164 2-Bromo- PhNH2

2444 164 2,3- Dichloro- PhNH2

2445 164  74

2446 164  75.60

2447 165  75.1

2448 165  75.49

2449 165  75.9

2450 165  75.44

2451 165  75.61

2452 165  75.20

2453 165 PhNH2

2454 165 2-Bromo- PhNH2

2455 165 2,3- Dichloro- PhNH2

2456 165  74

2457 165  75.60

2458 166  75.49

2459 166  75.9

2460 166  75.44

2461 166  75.61

2462 166  75.44

2463 166  75.20

2464 166  74

2465 166  75.60

2466 166 2-Bromo- PhNH2

2467 166 2,3- Dichloro- PhNH2

2468 167  75.1

2469 167  75.49

2470 167  75.9

2471 167  75.44

2472 167  75.61

2473 167  75.44

2474 167  75.20

2475 167  74

2476 167  75.60

2477 167 2-Bromo- PhNH2

2478 167 2,3- Dichloro- PhNH2

2479 168  75.1

2480 168  75.49

2481 168  75.9

2482 168  75.44

2483 168  75.61

2484 168  75.20

2485 168 PhNH2

2486 168 2-Bromo- PhNH2

2487 168 2,3- Dichloro- PhNH2

2488 168  74

2489 168  75.60

2600 253  75.1

2601 253  75.49

2602 253  75.9

2603 253  75.01E

2604 253  75.61

2605 253 1048

2606 253  75.69

2607 253  603B

2608 253  603E

2609 253  603F

2610 253  75.20

2611 253  74

2612 253 2-Bromo- PhNH2

2613 253 2,3- Dichloro- PhNH2

2614 22.26  75.1

2615 22.26  75.49

2616 22.26  75.9

2617 22.26  75.10E

2618 22.26  75.61

2619 22.26 1048

2620 22.26  75.69

2621 22.26  603B

2622 22.26  603E

2623 22.26  603F

2624 22.26  75.20

2625 22.26  74

2626 22.26 2-Bromo- PhNH2

2627 22.26 2,3- Dichloro- PhNH2

2628 22.6  75.1

2629 22.6  75.49

2630 22.6  75.9

2631 22.6  75.10E

2632 22.6  75.61

2633 22.6 1048

2634 22.6  75.69

2635 22.6  603B

2636 22.6  603E

2637 22.6  603F

2638 22.6  75.20

2639 22.6  74

2640 22.6 2-Bromo- PhNH2

2641 22.6 2,3- Dichloro- PhNH2

2642 22.7  75.1

2643 22.7  75.49

2644 22.7  75.9

2645 22.7  75.10E

2646 22.7  75.61

2647 22.7 1048

2648 22.7  75.69

2649 22.7  603B

2650 22.7  603E

2651 22.7  603F

2652 22.7  75.20

2653 22.7  74

2654 22.7 2-Bromo- PhNH2

2655 22.7 2,3- Dichloro- PhNH2

2656 22.22  75.1

2657 22.22  75.49

2658 22.22  75.9

2659 22.22  75.10E

2660 22.22  75.61

2661 22.22 1048

2662 22.22  75.69

2663 22.22  603B

2664 22.22  603E

2665 22.22  603F

2666 22.22  75.20

2667 22.22  74

2668 22.22 2-Bromo- PhNH2

2669 22.22 2,3- Dichloro- PhNH2

2670 22.19  75.1

2671 22.19  75.49

2672 22.19  75.9

2673 22.19  75.10E

2674 22.19  75.61

2675 22.19 1048

2676 22.19  75.69

2677 22.19  603B

2678 22.19  603E

2679 22.19  603F

2680 22.19  75.20

2681 22.19  74

2682 22.19 2-Bromo- PhNH2

2683 22.19 2,3- Dichloro- PhNH2

2684 250  75.1

2685 250  75.49

2686 250  75.9

2687 250  75.10E

2688 250  75.61

2689 250 1048

2690 250  75.69

2691 250  603B

2692 250  603E

2693 250  603F

2694 250  75.20

2695 250  74

2696 250 2-Bromo- PhNH2

2697 250 2,3- Dichloro- PhNH2

2698 22.28  75.1

2699 22.28  75.49

2700 22.28  75.9

2701 22.28  75.10E

2702 22.28  75.61

2703 22.28 1048

2704 22.28  75.69

2705 22.28  603B

2706 22.28  603E

2707 22.28  603F

2708 22.28  75.20

2709 22.28  74

2710 22.28 2-Bromo- PhNH2

2711 22.28 2,3- Dichloro- PhNH2

2712 251  75.1

2713 251  75.49

2713 251  75.9

2715 251  75.10E

2716 251  75.61

2717 251 1048

2718 251  75.69

2719 251  603B

2720 251  603E

2721 251  603F

2722 251  75.20

2723 251  74

2724 251 2-Bromo- PhNH2

2725 251 2,3- Dichloro- PhNH2

2726 252  75.1

2727 252  75.49

2728 252  75.9

2729 252  75.10E

2730 252  75.61

2731 252 1048

2732 252  75.69

2733 252  603B

2734 252  603E

2735 252  603F

2736 252  75.20

2737 252  74

2738 252 2-Bromo- PhNH2

2739 252 2,3- Dichloro- PhNH2

2800 350 PhNH2

2801 350 2-Bromo- PhNH2

2802 350 2,3- Dichloro- PhNH2

2803 350  74

2804 350  75.60

2806 350  75.49

2807 350  75.9

2808 350  75.61

2809 350  75.20

2810 350  75.44

2811 351 PhNH2

2812 351 2-Bromo- PhNH2

2813 351 2,3- Dichloro- PhNH2

2814 351  74

2815 351  75.60

2816 351  75.1

2817 351  75.49

2818 351  75.9

2819 351  75.61

2820 351  75.20

2821 351  75.44

2822 352 PhNH2

2823 352 2-Bromo- PhNH2

2824 352 2,3- Dichloro- PhNH2

2825 352  74

2826 352  75.60

2827 352  75.1

2828 352  75.49

2829 352  75.9

2830 352  75.61

2831 352  75.20

2832 352  75.44

2833 353 PhNH2

2834 353 2-Bromo- PhNH2

2835 353 2,3- Dichloro- PhNH2

2836 353  74

2837 353  75.60

2838 353  75.1

2839 353  75.49

2840 353  75.9

2841 353  75.61

2842 353  75.20

2843 353  75.44

2844 354 PhNH2

2845 354 2-Bromo- PhNH2

2846 354 2,3- Dichloro- PhNH2

2847 354  74

2848 354  75.60

2849 354  75.1

2850 354  75.49

2851 354  75.9

2852 354  75.61

2853 354  75.20

2854 354  75.44

2855 355 PhNH2

2856 355 2-Bromo- PhNH2

2857 355 2,3- Dichloro- PhNH2

2858 355  75.44

2859 355  75.60

2860 355  75.1

2861 355  75.49

2862 355  75.9

2863 355  75.61

2864 355  75.20

2865 355  75.44

2866 356 PhNH2

2867 356 2-Bromo- PhNH2

2868 356 2,3- Dichloro- PhNH2

2869 356  74

2870 356  75.60

2871 356  75.1

2872 356  75.49

2873 356  75.60

2874 356  75.61

2875 356  75.20

2876 356  75.44

2877 356 PhNH2

2878 356 2-Bromo- PhNH2

2879 356 2,3- Dichloro- PhNH2

2880 356  74

2881 356  75.60

2882 356  75.1

2883 356  75.49

2884 356  75.9

2885 356  75.61

2886 356  75.20

2887 356  75.44

3000 450 PhNH2

3001 450 2-Bromo- PhNH2

3002 450 2,3- Dichloro- PhNH2

3003 450  74

3004 450  75.60

3005 450  75.1

3006 450  75.61

3007 450  75.49

3008 450  75.9

3009 450  75.44

3010 450  75.20

3011 451 PhNH2

3012 451 2-Bromo- PhNH2

3013 451 2,3- Dichloro- PhNH2

3014 451  74

3015 451  75.60

3016 451  75.1

3017 451  75.61

3018 451  75.49

3019 451  75.9

3020 451  75.44

3021 451  75.20

3022 452 PhNH2

3023 452 2-Bromo- PhNH2

3024 452 2,3- Dichloro- PhNH2

3025 452  74

3026 452  75.60

3027 452  75.1

3028 452  75.61

3029 452  75.49

3030 452  75.9

3031 452  75.44

3032 452  75.20

3033 453 PhNH2

3034 453 2,3- Bromo- PhNH2

3035 453 2,3- Dichloro- PhNH2

3036 453  74

3037 453  75.60

3038 453  75.1

3039 453  75.61

3040 453  75.49

3041 453  75.9

3042 453  75.44

3043 453  75.20

3044 454 PhNH2

3045 454 2-Bromo- PhNH2

3046 454 2,3- Dichloro- PhNH2

3047 454  74

3048 454  75.60

3049 454  75.1

3050 454  75.61

3051 454  75.49

3052 454  75.9

3053 454  75.44

3054 454  75.20

3055 455 PhNH2

3056 455 2-Bromo- PhNH2

3057 455 2,3- Dichloro- PhNH2

3058 455  74

3059 455  75.60

3060 455  75.1

3061 455  75.61

3062 455  75.49

3063 455  75.9

3064 455  75.44

3065 455  75.20

3066 456 PhNH2

3067 456 2-Bromo- PhNH2

3068 456 2,3- Dichloro- PhNH2

3069 456  74

3070 456  75.60

3071 456  75.1

3072 456  75.61

3073 456  75.49

3074 456  75.9

3075 456  75.44

3076 456  75.20

3077 457 PhNH2

3078 457 2-Bromo- PhNH2

3079 457 2,3- Dichloro- PhNH2

3080 457  74

3081 457  75.60

3082 457  75.1

3083 457  75.61

3084 457  75.49

3085 457  75.9

3086 457  75.44

3087 457  75.20

Example 1

To a stirred solution of the thiadiazole-monoxide from Preparative Example 2001.5 (15.0 mg, 0.0336 mmol) in anhydrous dichloromethane at 0° C. was added triphenylphosphine (44 mg, 0.1681 mmol) followed by the drop-wise addition of carbon tetrachloride (1.0 mL). The reaction mixture was warmed to 40-45° C. and stirred for 2-3 hours. The mixture was cooled to room temperature, solvents were removed under reduced pressure and the product was purified by preparative thin layer chromatography using dichloromethane-methanol (20:1) to afford the title compound as a white solid. (6 mg, 43%, m.p=65° C.).

Examples 2-4 and 6-35

Following a similar procedure to that set forth in Example 1, but using the thiadiazoleoxide intermediate from the Preparative Example indicated in the Table below, the thiadiazole products in the Table below were prepared.

Prep Ex of Thiadiazole 1. Yield oxide 2. mp (° C.) Ex. Intermediate Product 3. MH⁺ 2 2000

1. 18% 2. 80 3. 398 3 2001.3

1. 30% 2. 72 3. 416 4 2001.4

1. 21% 2. 62 3. 402 6 2001.6

1. 9% 2. 60 3. 430 7 2001.7

1. 21% 2. 70 3. 402 8 2001.8

1. 13% 2. 3. 279 (M − 191) 9 2001.9

1. 60% 2. 69 3. 424 10 2001.10

1. 57% 2. 69 3. 424 11 2001.11

1. 19% 2. 66 3. 428 12 2001.12

1. 59% 2. 86 3. 364 13 2001.13

1. 56% 2. 86 3. 364 14 2001.14

1. 23% 2. 69 3. 442 15 2001.15

1. 40% 2. 100 3. 440 16 2001.16

1. 8% 2. 78 3. 438 17 2001.17

1. 12% 2. 76 3. 470 18 2001.18

1. 8% 2. 92 3. 400 19 2001.19

1. 35% 2. 78 3. 434 20 2001.20

1. 46% 2. 86 3. 410 21 2001.21

1. 11% 2. 96 3. 444 22 2001.22

1. 19% 2. 93 3. 466 23 2001.23

1. 36% 2. 215 3. 466 24 2001.24

1. 42% 2. 73 3. 441 25 2001.39

1. 19% 2. 71 3. 432 26 2001.43

1. 26% 2. 120 3. 430.1 27 2001.42

1. 27% 2. 66 3. 374.1 28 2001.41

1. 33% 2. 70 3. 496.1 29 2001.52

1. 3% 2. 119 3. 496.1 30 2001.53

1. 8% 2. 70 3. 442.1 31 2001.48

1. 10% 2. 74 3. 416.1 32 2001.54

1. 4% 2. 86 3. 458.1 33 2001.50

1. 52% 2. 123 3. 484.1 34 2001.51

1. 66% 2. 90 3. 462.1 35 2001.49

1. 71% 2. 65 3. 470.1

Examples 100-105, 107, 108, 110, 111, 112, 114, 115, 116, 118-132, 134-145, 148, 180, 182, 183, 185, 186, and 188

If one were to follow a procedure similar to that set forth in Example 1, but using the thiadiazoleoxide intermediate from the Preparative Example indicated in the Table below, the thiadiazole products in the Table below could be obtained.

Prep Ex of Thiadiazole oxide Ex. Intermediate Product 100 2255

101 2256

103 2238

104 2239

105 2001.2

107 2257

108 2258

110 2259

111 2262

112 2260

114 2263

115 2264

116 2229

118 2265

119 2266

120 2211

121 2267

122 2268

123 2269

124 2270

125 2271

126 2272

127 2273

128 2274

129 2223

130 2275

131 2217

132 2276

134 2277

135 2278

136 2279

137 2280

138 2281

139 2282

140 2283

141 2284

142 2285

143 2206

144 2286

145 2287

148 2289

180 2250

182 2251A

183 2251B

185 2251C

186 2252

188 2254

Examples 300-389, 500-639, 700-787, and 900-987

Following a similar procedure to that set forth in Example 1, but using the thiadiazoleoxide intermediate from the Preparative Example indicated in the Table below, the thiadiazole products in the Table below could be prepared.

Prep. of mono-ox Ex compd Product 300 2400

301 2402

302 2402

303 2403

304 2404

305 2405

306 2406

307 2001.25

308 2408

309 2409

310 2410

311 2411

312 2412

313 2413

314 2414

315 2415

316 2416

317 2417

318 2418

319 2419

320 2420

321 2421

322 2422

323 2423

324 2424

325 2425

326 2426

327 2427

328 2428

329 2429

330 2430

331 2431

332 2432

333 2433

334 2434

335 2435

336 2436

337 2437

338 2438

339 2439

340 2440

341 2441

342 2442

343 2443

344 2444

345 2445

346 2446

347 2447

348 2448

349 2449

350 2450

351 2451

352 2452

353 2453

354 2454

355 2455

356 2456

357 2457

358 2458

359 2459

360 2460

361 2461

362 2462

363 2463

364 2464

365 2465

366 2466

367 2467

368 2468

369 2469

370 2470

371 2471

372 2472

373 2473

374 2474

375 2475

376 2476

377 2477

378 2478

379 2479

380 2480

381 2481

382 2482

383 2483

384 2484

385 2485

386 2486

387 2487

388 2488

389 2489

500 2600

501 2601

502 2602

503 2603

504 2604

505 2605

506 2606

507 2607

508 2608

509 2609

510 2610

511 2611

512 2612

513 2613

514 2614

515 2615

516 2616

517 2617

518 2618

519 2619

520 2620

521 2621

522 2622

523 2623

524 2624

525 2625

526 2626

527 2627

528 2628

529 2629

530 2630

531 2631

532 2632

533 2633

534 2634

535 2635

536 2636

537 2637

538 2638

539 2639

540 2640

541 2641

542 2642

543 2643

544 2644

545 2645

546 2646

547 2647

548 2648

549 2649

550 2650

551 2651

552 2652

553 2653

554 2654

555 2655

556 2656

557 2657

558 2658

559 2659

560 2660

561 2661

562 2662

563 2663

564 2664

565 2665

566 2666

567 2667

568 2668

569 2669

570 2670

571 2671

572 2672

573 2673

574 2674

575 2675

576 2676

577 2677

578 2678

579 2679

580 2680

581 2681

582 2682

583 2683

584 2684

585 2685

586 2686

587 2687

588 2688

589 2689

590 2690

591 2691

592 2692

593 2693

594 2694

595 2695

596 2696

597 2697

598 2698

599 2699

600 2700

601 2701

602 2702

603 2703

604 2704

605 2705

606 2706

607 2707

608 2708

609 2709

610 2710

611 2711

612 2712

613 2713

614 2713

615 2715

616 2716

617 2717

618 2718

619 2719

620 2720

621 2721

622 2722

623 2723

624 2724

625 2725

626 2726

627 2727

628 2728

629 2729

630 2730

631 2731

632 2732

633 2733

634 2734

635 2735

636 2736

637 2737

638 2738

639 2739

700 2800

701 2801

702 2802

703 2803

704 2804

705 2805

706 2806

707 2807

708 2808

709 2809

710 2810

711 2811

712 2812

713 2813

714 2814

715 2815

716 2816

717 2817

718 2818

719 2819

720 2820

721 2821

722 2822

723 2823

724 2824

725 2825

726 2826

727 2827

728 2828

729 2829

730 2830

731 2831

732 2832

733 2833

734 2834

735 2835

736 2836

737 2837

738 2838

739 2839

740 2840

741 2841

742 2842

743 2843

744 2844

745 2845

746 2846

747 2847

748 2848

749 2849

750 2850

751 2851

752 2852

753 2853

754 2854

755 2855

756 2856

757 2857

758 2858

759 2859

760 2860

761 2861

762 2862

763 2863

764 2864

765 2865

766 2866

767 2867

768 2868

769 2869

770 2870

771 2871

772 2872

773 2873

774 2874

775 2875

776 2876

777 2877

778 2878

779 2879

780 2880

781 2881

782 2882

783 2883

784 2884

785 2885

786 2886

787 2887

900 3000

901 3001

902 3002

903 3003

904 3004

905 3005

906 3006

907 3007

908 3008

909 3009

910 3010

911 3011

912 3012

913 3013

914 3014

915 3015

916 3016

917 3017

918 3018

919 3019

920 3020

921 3021

922 3022

923 3023

924 3024

925 3025

926 3026

927 3027

928 3028

929 3029

930 3030

931 3031

932 3032

933 3033

934 3034

935 3035

936 3036

937 3037

938 3038

939 3039

940 3040

941 3041

942 3042

943 3043

944 3044

945 3045

946 3046

947 3047

948 3048

949 3049

950 3050

951 3051

952 3052

953 3053

954 3054

955 3055

956 3056

957 3057

958 3058

959 3059

960 3060

961 3061

962 3062

963 3063

964 3064

965 3065

966 3066

967 3067

968 3068

969 3069

970 3070

971 3071

972 3072

973 3073

974 3074

975 3075

976 3076

977 3077

978 3078

979 3079

980 3080

981 3081

982 3082

983 3083

984 3084

985 3085

986 3086

987 3087

Examples of disease-modifying antirheumatic drugs include, for example, methotrexate, sulfasalzine, leflunomide, TNFα directed agents (e.g., infliximab, etanercept, and adalimumab), IL-1 directed agents (e.g., anakinra) B cell directed agents (e.g., rituximab), T cell directed agents (e.g., alefacept, efalizumab, and CTLA4-Ig), TNFα-converting enzyme inhibitors, interleukin-1 converting enzyme inhibitors, and p38 kinase inhibitors.

The term “other classes of compounds indicated for the treatment of rheumatoid arthritis”, as used herein, unless indicated otherwise, means: compounds selected from the group consisting of: IL-1 directed agents (e.g., anakinra); B cell directed agents (e.g., rituximab); T cell directed agents (e.g., alefacept, efalizumab, and CTLA4-Ig), TNFα-converting enzyme inhibitors, interleukin-1 converting enzyme inhibitors, and p38 kinase inhibitors.

Angina is a CXCR2 mediated disease treatable with the CXCR2 antagonist compounds of this invention. Thus, another embodiment of this invention is directed to a method of treating angina in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound (a CXCR2 antagonist compound) of formula IA.

While the present invention has been described in conjunction with specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention. 

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein: A is:

wherein each R⁹ is independently selected from the group consisting of: H and halogen; B is

R² is —OH; R³ is selected from the group consisting of: hydrogen, cyano, halogen, alkyl, alkoxy, cycloalkyl substituted with 1 to 4 alkyl groups wherein each alkyl group is independently selected, unsubstituted cycloalkyl, cycloalkyl substituted with 1 to 4 alkyl groups, —OH, —CF₃, —OCF₃, —NO₂, —C(O)R¹³, —C(O)OR¹³, —C(O)NHR¹⁷, —C(O)NR¹³R¹⁴, —SO_((t))NR¹³R¹⁴, —SO_((t))R¹³, —C(O)NR¹³OR¹⁴, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl,

wherein there are 1 to 6 substituents on said substituted aryl group and each substituent is independently selected from the group consisting of: a) halogen, b) —CF₃, c) —COR¹³, d) —OR¹³, e) —NR¹³R¹⁴, f) —NO₂, g) —CN, h) —SO₂OR¹³, i) —Si(alkyl)₃, wherein each alkyl is independently selected, j) —Si(aryl)₃, wherein each alkyl is independently selected, k) —(R¹³)₂R¹⁴Si, wherein each R¹³is independently selected, l) —CO₂R¹³, m) —C(O)NR¹³R¹⁴, n) —SO₂NR¹³R¹⁴, o) —SO₂R¹³, p) —OC(O)R¹³, q) —OC(O)NR¹³R¹⁴, r) —NR¹³C(O)R¹⁴, and s) —NR¹³CO₂R¹⁴; and wherein there are 1 to 6 substituents on said substituted heteroaryl group and each substituent is independently selected from the group consisting of: a) halogen, b) —CF₃, c) —COR¹³, d) —OR¹³, e) —NR¹³R¹⁴, f) —NO₂, g) —CN, h) —SO₂OR¹³, i) —Si(alkyl)₃, wherein each alkyl is independently selected, j) —Si(alkyl)₃, wherein each alkyl is independently selected, k) —(R¹³)₂R¹⁴Si, wherein each R¹³ is independently selected, l) —CO₂R¹³, m) —C(O)NR¹³R¹⁴, n) —SO₂NR¹³R¹⁴, o) —SO₂R¹³, p) —OC(O)R¹³, q) —OC(O)NR¹³R¹⁴, r) —NR¹³C(O)R¹⁴, and s) —NR¹³CO₂R¹⁴; Each R⁴, R⁵ R⁶ independently selected from the group consisting of: hydrogen, halogen, alkyl and —CF₃; each R⁷ and R⁸ is independently selected from the group consisting of: H and unsubstituted alkyl; each R¹³ and R¹⁴ is independently selected from the group consisting of: H, unsubstituted or substituted alkyl, unsubstituted or substituted cyanoalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cyanocycloalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted fluoroalkyl, and unsubstituted or substituted heterocycloalkylalkyl; wherein there are 1 to 6 substituents on said substituted R¹³ and R¹⁴ groups and each substituent is independently selected from the group consisting of: alkyl, —CF₃, —OH, alkoxy, aryl, arylalkyl, fluroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, —N(R⁴⁰)₂, —C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —S(O)_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, halogen, —NHC(O)NR¹⁵R¹⁶ and —SO₂R¹⁵ provided that R¹⁵ is not H; and provided that for the substituted cyanoalkyl and the substituted cyanocycloalkyl moieties the carbon atom to which the cyano group is bound to does not also have bound to said carbon atom a substituent selected from the group consisting of: —OH, alkoxy, —N(R⁴⁰)₂, halogen and —NHC(O)NR¹⁵R¹⁶; or R¹³ and R¹⁴ taken together with the nitrogen they are attached to in the groups —C(O)NR¹³R¹⁴ and —SO₂NR¹³R¹⁴ form an unsubstituted or substituted saturated heterocyclic ring, said ring optionally containing one additional heteroatom selected from the group consisting of: O, S and NR¹⁸; wherein there are 1 to 3 substituents on the substituted cyclized R¹³ and R¹⁴ groups and each substituent is independently selected from the group consisting of: CN, alkyl, cyanoalkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, cyanocycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, —C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵ (provided that R¹⁵ is not H), —NHC(O)NR¹⁵R¹⁶, —NHC(O)OR¹⁵, halogen, and a heterocycloalkenyl group; and provided that the carbon atom to which the cyano group is bound to does not also have bound to said carbon atom a substituent selected from the group consisting of: hydroxy, alkoxy, amino, halogen, —NHC(O)NR¹⁵R¹⁶ and —NHC(O)OR¹⁵; each R¹⁵ and R¹⁶ is independently selected from the group consisting of: H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl; R¹⁷ is selected from the group consisting of: —SO₂alkyl, —SO₂aryl, —SO₂cycloalkyl, and —SO₂heteroaryl; R¹⁸ is selected from the group consisting of: H, alkyl, aryl, heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹ and —C(O)NR¹⁹R²⁰; each R¹⁹ and R²⁰ is independently selected from the group consisting of: alkyl, aryl and heteroaryl; R³⁰ is selected from the group consisting of: alkyl, cycloalkyl, —CN, —NO₂, or —SO₂R¹⁵ provided that R¹⁵ is not H; each R³¹ is independently selected from the group consisting of: unsubstituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl and unsubstituted or substituted cycloalkyl; wherein there are 1 to 6 substituents on said substituted R³¹ groups and each substituent is independently selected from the group consisting of: alkyl, halogen and —CF₃; each R⁴⁰ is independently selected from the group consisting of: H, alkyl and cycloalkyl; and t is 0, 1 or
 2. 2. The compound of claim 1 wherein A is:


3. The compound of claim 1 wherein B is selected from the group consisting of:


4. The compound of claim 1 wherein B is selected from the group consisting of:


5. The compound of claim 1 wherein B is selected from the group consisting of:

wherein R² is —OH; and

wherein R² is —OH, and R¹³ and R¹⁴ are independently selected from the group consisting of H and alkyl.
 6. The compound of claim 1 wherein: (1) substituent A in formula IA is of:

(2) substituent B in formula IA is of:

wherein: R² is —OH; R⁴ is selected form the group consisting of: H, Br, —CH₃, ethyl and —CF₃; R⁵ is H; R⁶ is selected from the group consisting of: H, —CH₃ and —CF₃; and R¹³ and R¹⁴ are independently selected from the group consisting of H and methyl.
 7. A pharmaceutically acceptable salt of a compound of claim
 1. 8. A sodium or calcium salt of a compound of claim
 1. 9. The compound of claim 1 selected from the group consisting of

and the pharmaceutically acceptable salts thereof.
 10. The compound of claim 1 in isolated and pure form.
 11. A pharmaceutical composition comprising at least one compound of claim 1, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.
 12. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein: A is:

B is

R² is —OH; R³ is selected from the group consisting of: —C(O)NR¹³R¹⁴ and —SO_((t))NR¹³R¹⁴; Each R⁴, R⁵ and R⁶ is independently selected from the group consisting of: hydrogen, halogen, alkyl and —CF₃; each R⁷ and R⁸ is independently selected from the group consisting of: H and unsubstituted alkyl; each R¹³ and R¹⁴ independently selected from the group consisting of: H, unsubstituted alkyl; or R¹³ and R¹⁴ taken together with the nitrogen they are attached to in the groups —C(O)NR¹³R¹⁴ and —SO₂NR¹³R¹⁴ form an unsubstituted or substituted saturated heterocyclic ring, said ring optionally containing one additional heteroatom selected from the group consisting of: O, S and NR¹⁸; wherein there are 1 to 3 substituents on the substituted cyclized R¹³ and R¹⁴ groups and each substituent is independently selected from the group consisting of: CN, alkyl, cyanoalkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, cyanocycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, —C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵ (provided that R¹⁵ is not H), —NHC(O)NR¹⁵R¹⁶—NHC(O)OR¹⁵, halogen, and a heterocycloalkenyl group; and provided that the carbon atom to which the cyano group is bound to does not also have bound to said carbon atom a substituent selected from the group consisting of: hydroxy, alkoxy, amino, halogen, —NHC(O)NR¹⁵R¹⁶ and —NHC(O)OR¹⁵; each R¹⁵and R¹⁶ is independently selected from the group consisting of: H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl; R¹⁷ is selected from the group consisting of: —SO₂alkyl, —SO₂aryl, —SO₂cycloalkyl, and —SO₂heteroaryl; R¹⁸ is selected from the group consisting of: H, alkyl, aryl, heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹ and —C(O)NR¹⁹R²⁰; each R¹⁹ and R²⁰ is independently selected from the group consisting of: alkyl, aryl and heteroaryl; R³⁰ is selected from the group consisting of: alkyl, cycloalkyl, —CN, —NO₂, or —SO₂R¹⁵ provided that R¹⁵ is not H; each R³¹ is independently selected from the group consisting of: unsubstituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl and unsubstituted or substituted cycloalkyl; wherein there are 1 to 6 substituents on said substituted R³¹ groups and each substituent is independently selected from the group consisting of: alkyl, halogen and —CF₃; each R⁴⁰ is independently selected from the group consisting of: H, alkyl and cycloalkyl; and t is 0, 1 or
 2. 13. The compound of claim 12 wherein each R¹³ and R¹⁴ independently selected from the group consisting of: H, unsubstituted alkyl.
 14. The compound of claim 12 wherein R³ is —C(O)NR¹³R¹⁴.
 15. The compound of claim 13 wherein R³ is —C(O)NR¹³R¹⁴.
 16. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein: A is:

B is

R² is —OH; R³ is selected from the group consisting of: —C(O)NR¹³R¹⁴; Each R⁴, R⁵ and R⁶ is independently selected from the group consisting of: hydrogen, halogen, alkyl and —CF₃; each R⁷ and R⁸ is independently selected from the group consisting of: H and unsubstituted alkyl; each R¹³ and R¹⁴ is independently selected from the group consisting of: H, unsubstituted alkyl; and t is 0, 1 or
 2. 17. The compound of claim 12 selected from the group consisting of:


18. The compound of claim 16 selected from the group consisting of:


19. The compound of claim 12 selected from the group consisting of: 